Optimal PEEP Obtained by Titrating Inspiratory Oxygen Fraction Versus Electrical Impedance Tomography in Patients with High Risk of Intraoperative Atelectasis: A Randomized Controlled Trial

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors of “Bioengineering-4187940”

First of all, I would like to congratulate you on this thorough and expansive presentation of your work. Unfortunately, even though your article has the above characteristics and even more, I need to point out some additions – changes to enhance its appeal. All of those, stem from the fact that your paper would be better suited for publication with in a different type of journal. I believe this paper, in its current form may be more appropriate for publication in an anesthesiology, respiratory medicine, critical care, or physiology journal. Your extensive use of terminology and processes that stem from the above sciences might make your article difficult to comprehend from readers that lack this specialized knowledge. If, however, you choose to continue your efforts with the “bioengineering journal” then more insights in describing the technical aspects of electric impedance tomography are needed. I would include a more detailed description of the hardware, software and interface (description of the belt and its attachments in the machine). I would also describe a more detailed physiological theory behind its use, since those technicalities might of more interest to the bioengineer audience. I would also include several color pictures from the screen, showing recruitable, unrecruitable and over distended lung areas. These additions I would also keep if I was to go the alternative journal group. However, in that case I would also emphasize the fluctuations of ETCO2 and PaCO2, due to the abdominal insufflation by CO2, its breach in to the circulation and exit through the alveoli. I would do this because in the PCO2 gap may be clinically used to track dead space fluctuations, however this is difficult to interpret in laparoscopic surgery. So, I would present a paragraph with a quick description of the physiology and I would include those readings in my charts, acknowledging the bias presented by CO2 abdominal insufflation. If MDPI presented you with an invitation to send your work in the bioengineering journal, then I would try and include the above proposals. However, since I myself has a background of anesthesiology and critical care and am proficient in the methods you described, I think that your article would benefit people with our background in those types of journals that I wrote of at the beginning.

Thank you for your excellent paper, your effort and time. I hope you find my remarks useful and continue with your publication

Author Response

Comment: First of all, I would like to congratulate you on this thorough and expansive presentation of your work. Unfortunately, even though your article has the above characteristics and even more, I need to point out some additions – changes to enhance its appeal. All of those, stem from the fact that your paper would be better suited for publication with in a different type of journal. I believe this paper, in its current form may be more appropriate for publication in an anesthesiology, respiratory medicine, critical care, or physiology journal. Your extensive use of terminology and processes that stem from the above sciences might make your article difficult to comprehend from readers that lack this specialized knowledge. If, however, you choose to continue your efforts with the “bioengineering journal” then more insights in describing the technical aspects of electric impedance tomography are needed. I would include a more detailed description of the hardware, software and interface (description of the belt and its attachments in the machine). I would also describe a more detailed physiological theory behind its use, since those technicalities might of more interest to the bioengineer audience. I would also include several color pictures from the screen, showing recruitable, unrecruitable and over distended lung areas. These additions I would also keep if I was to go the alternative journal group. However, in that case I would also emphasize the fluctuations of ETCO2 and PaCO2, due to the abdominal insufflation by CO2, its breach in to the circulation and exit through the alveoli. I would do this because in the PCO2 gap may be clinically used to track dead space fluctuations, however this is difficult to interpret in laparoscopic surgery. So, I would present a paragraph with a quick description of the physiology and I would include those readings in my charts, acknowledging the bias presented by CO2 abdominal insufflation. If MDPI presented you with an invitation to send your work in the bioengineering journal, then I would try and include the above proposals. However, since I myself has a background of anesthesiology and critical care and am proficient in the methods you described, I think that your article would benefit people with our background in those types of journals that I wrote of at the beginning.

 

Thank you for your excellent paper, your effort and time. I hope you find my remarks useful and continue with your publication.

Response: We would like to express our sincere gratitude for your thorough, constructive, and valuable comments on our manuscript and your suggestions have provided clear guidance for improving our manuscript and clarifying its positioning. After careful discussion among the research team, we do our best efforts to revise the manuscript to better meet the requirements of Bioengineering. We fully understand that the extensive use of anesthesiology- and critical care-related terminology and processes may hinder the comprehension of readers without specialized knowledge in these fields. In response to this, we will make the following key revisions to enhance the technical appeal of the manuscript for the bioengineer audience:

• Add a detailed description of the EIT monitoring technique used in the present study, which was described as “For Group PEEPEIT, the global and reginal lung ventilation were continuously monitored and recorded by EIT (PulmoVista500, Draeger Medical, Luebeck, Germany). In the present study, an EIT electrode belt, which carries 16 electrodes with a width of 40 mm, was placed around the thorax in the fifth intercostal space, and a reference electrode was placed on the right thorax. A customized PEEP titration also started from 18 cmH2O and decreased by 2 cmH2O stepwise for 5 min as described previously,10 during the room air ventilation. The optimal PEEPEIT value was defined as the intercept of cumulated collapse and overdistension percentage curves to minimize regional compliance loss, which was analyzed by Costas algorithm using customized software. If the regional compliance decreases with the increase of PEEP, it indicates that the region may have excessive expansion. If the regional compliance decreases with the decrease of PEEP, it indicates that the region may collapse. We used changes in compliance to determine whether there is lung collapse and atelectasis”. It was added in “Method” section on page 4 and was marked in red.

 

• Supplement color images of lung areas from the EIT screen, which showed recruitable, unrecruitable and over distended lung areas. It was added to revised Supplementary Fig. S2 on page 14.

Furthermore, we also sincerely appreciate the editor’s insightful comment on the influence of CO₂ pneumoperitoneum. We agree with the bias presented by CO2 abdominal insufflation; carbon dioxide pneumoperitoneum significantly affects respiratory physiology during laparoscopic surgery. Absorption of CO₂ from the peritoneal cavity increases systemic CO₂ load, leading to elevated PaCO₂ and ETCO₂ levels as excess gas is eliminated via the alveoli. This process alters the arterial-to-end-tidal CO₂ gradient and complicates interpretation of the PCO₂ gap, which is often used to estimate physiological dead space. Therefore, fluctuations in dead-space parameters cannot be attributed solely to changes in alveolar recruitment or ventilation-perfusion matching, but are also confounded by CO₂ resorption. Accordingly, all respiratory and dead-space measurements were interpreted with consideration of this physiological bias. In the present study, we also reported PCO₂ values at multiple time points in the Results section in Table3, which may demonstrate the impact of CO₂ pneumoperitoneum on arterial carbon dioxide tension.

Reviewer 2 Report

Comments and Suggestions for Authors

This is a well‑designed RCT addressing a clinically relevant question: whether FiO₂‑guided PEEP titration can serve as a practical alternative to EIT‑guided titration in high‑risk intraoperative atelectasis. The manuscript is generally clear, methodologically sound, and supported by appropriate statistical analysis. The topic is timely and has potential clinical impact.

Suggestions:
The authors repeatedly state the difference is “not clinically significant,” but this is asserted rather than demonstrated. For example: “The difference of 2 cmH₂O… is considered clinically insignificant.”
Recommendation: Provide supporting evidence or sensitivity analyses showing that outcomes (oxygenation, compliance, hemodynamics) do not meaningfully diverge across this 2 cmH₂O range.
The authors acknowledge:
“we may have underestimated the optimal PEEP using EIT because our titration began at 18 cmH₂O.”
This is a nontrivial limitation because EIT‑derived optimal PEEP may exceed 18 cmH₂O in Trendelenburg + pneumoperitoneum.
Recommendation: Clarify how many patients reached the upper limit and whether this could systematically bias the comparison.
The authors state:
“we did not perform intraoperative or postoperative CT scans… we could not determine if improved oxygenation… translates to better outcomes.”
Given that the study’s premise is atelectasis prevention, absence of imaging limits mechanistic interpretation.
Recommendation: Acknowledge explicitly that oxygenation and compliance are surrogate markers, not direct measures of atelectasis.
Both groups were extubated at their individualized optimal PEEP. Thus postoperative hypoxemia and PPCs cannot differentiate the two titration methods. The authors note:
Recommendation: Clarify that postoperative outcomes reflect the effect of maintaining optimal PEEP, not the titration method.
Some tables report standardized mean differences without interpretation. Repeated-measures ANOVA results (Pw, Pb) are difficult to interpret without clearer labeling.
Recommendation: Add a brief explanation of Pw and Pb in the table footnotes and consider simplifying the presentation.

Author Response

Comment1: The authors repeatedly state the difference is “not clinically significant,” but this is asserted rather than demonstrated. For example: “The difference of 2 cmH₂O… is considered clinically insignificant.”

Recommendation: Provide supporting evidence or sensitivity analyses showing that outcomes (oxygenation, compliance, hemodynamics) do not meaningfully diverge across this 2 cmH₂O range.

Response: We sincerely appreciate this thoughtful and constructive comment. In the present study, although the 2cmH₂O difference was associated with significantly differences in oxygenation and lung compliance, there was no significantly difference in the clinically relevant endpoint outcomes, including the incidence of hypoxemia and postoperative pulmonary complications, so we reached this  “not clinically significant”conclusion. Given that these key patient-centered outcomes did not differ meaningfully across this pressure range, we considered the 2cmH₂O variation to be not clinically significant.

 

Comment 2: The authors acknowledge:

“we may have underestimated the optimal PEEP using EIT because our titration began at 18 cmH₂O.”

This is a nontrivial limitation because EIT‑derived optimal PEEP may exceed 18 cmH₂O in Trendelenburg + pneumoperitoneum.

Recommendation: Clarify how many patients reached the upper limit and whether this could systematically bias the comparison.

Response: We appreciate the reviewer’s important comment regarding the upper limit of PEEP titration in the EIT group. Due to the principle of EIT-guided PEEP titration, we decreased PEEP stepwise from 18 cmH₂O to identify the optimal level. As a result, we cannot definitively determine how many patients in the EIT group had a true optimal PEEP exceeding 18 cmH₂O, since titration was stopped at this predefined upper limit.

However, based on observations from the SpO₂-guided group, in which PEEP was titrated to a higher range, none of the patients requiring PEEP above 18 cmH₂O (Showed on figure 2). Therefore, we believe that the number of patients in the EIT group whose optimal PEEP may have been underestimated is likely limited, and that this constraint is unlikely to introduce substantial systematic bias between groups.

 

Comment 3: The authors state:

“we did not perform intraoperative or postoperative CT scans… we could not determine if improved oxygenation… translates to better outcomes.”

Given that the study’s premise is atelectasis prevention, absence of imaging limits mechanistic interpretation.

Recommendation: Acknowledge explicitly that oxygenation and compliance are surrogate markers, not direct measures of atelectasis.

Response: We appreciate the reviewer’s valuable comment. We fully agree that the lack of intraoperative or postoperative CT imaging is an important limitation, and we added “oxygenation and lung compliance are surrogate markers, rather than direct, imaging‑based measures of atelectasis” to revised manuscript in “Discussion” section on page 13.

 

Comment 4: Both groups were extubated at their individualized optimal PEEP. Thus postoperative hypoxemia and PPCs cannot differentiate the two titration methods. The authors note:

Recommendation: Clarify that postoperative outcomes reflect the effect of maintaining optimal PEEP, not the titration method.

Response: We sincerely thank the reviewer for this insightful comment, which helps us clarify a key point in our manuscript. We agree that the similar rates of postoperative hypoxemia and PPCs between the two groups are primarily attributable to the common practice of extubating all patients at their individualized optimal PEEP, not the titration method. This was, in fact, our original intention to convey: both titration methods were equally effective in identifying a PEEP level that, when maintained, led to comparable postoperative pulmonary outcomes.​

 

Comment 5: Some tables report standardized mean differences without interpretation. Repeated-measures ANOVA results (Pw, Pb) are difficult to interpret without clearer labeling.

Recommendation: Add a brief explanation of Pw and Pb in the table footnotes and consider simplifying the presentation.

Response: We appreciate the reviewer’s constructive comment on the clarity of our statistical presentation. We acknowledge that standardized mean differences were not fully interpreted in the tables, and that the labels for repeated-measures ANOVA results (Pw, Pb) were insufficiently explained. To address this, we have:1) Added brief interpretations for all standardized mean differences in the footnotes of table1-2 on page 7-8. 2)Included clear definitions of Pw (P-value for within-subject effects) and Pb (P-value for between-group effects) in the table3’ footnotes on page 10.

Reviewer 3 Report

Comments and Suggestions for Authors

This research presents a randomized controlled study evaluating methods to determine optimal intraoperative positive end-expiratory pressure (PEEP) in patients undergoing robotic-assisted laparoscopic prostatectomy. This research requires MAJOR revision as the followings:

1. The manuscript should clearly state the research gap addressed and explain its significance
2.  
3. The study should better discuss limitations and their potential impact on results interpretation and overall study validity and reliability.
4. A comparison with existing methods should be strengthened to highlight differences, advantages, and clinical implications more clearly for readers.
5. Justification for the sample size should be provided, including assumptions, power analysis, and relevance to detecting meaningful clinical differences.
6. Potential sources of bias should be addressed, including selection, measurement, and analysis biases that may influence study outcomes significantly.
7. Applicability to broader patient groups should be clarified, especially regarding different risk profiles, comorbidities, and clinical settings beyond study population.
8. Key clinical outcomes should be more clearly defined, including their measurement methods, timing, and relevance to patient-centered care and practice.
9. Future research directions should be explicitly proposed, focusing on validation studies, diverse populations, and long-term clinical outcomes assessment.
10. Additional sections should be considered for better structure, such as expanded discussion, methodological clarification, or enhanced background context for readers.
11. Important findings should be explained in greater depth, emphasizing underlying mechanisms, clinical implications, and consistency with previous related studies.

Author Response

Comment 1: The manuscript should clearly state the research gap addressed and explain its significance

Response: Thank you for this important comment. We agree that the introduction could more clearly articulate the specific research gap and its clinical significance. In the revised manuscript, we have strengthened the opening section as “Electrical Impedance Tomography (EIT) offers a real-time, radiation-free method to visualize regional lung ventilation and identify the PEEP level that minimizes alveolar collapse and overdistension. And it has shown promise in reducing postoperative pulmonary complications. However, its application can be challenging and unsuitable for certain types of surgeries. Furthermore, its availability is limited, and its cost-effectiveness has yet to be established. Therefore, there is a demand for the development of new practical techniques to determine and maintain optimal intraoperative PEEP” in the “Introduction” section of revised manuscript on page 2.

 

 

Comment 2: The study should better discuss limitations and their potential impact on results interpretation and overall study validity and reliability.

Response: Thank you for this important comment. We agree that a more thorough and nuanced discussion of the study's limitations is essential for a proper interpretation of the findings. In the revised manuscript, we have significantly expanded the "Limitations" section(on page 12-13) to address the following key points and their potential impact on validity, generalizability, and reliability.

 

Comment 3: A comparison with existing methods should be strengthened to highlight differences, advantages, and clinical implications more clearly for readers.

Response: Thank you for this constructive suggestion. The primary objective of this study was to validate the SpO₂-guided PEEP titration method. We specifically chose the EIT-guided method as the active comparator because EIT is currently considered a reference standard for individualized PEEP titration in research settings, owing to its ability to directly assess regional lung mechanics. According to your suggestion, In the revised manuscript, we highlight the comparison of previous methods with red markings on page 11-12, which was expressed as” Optimal PEEP can be obtained using a variety of techniques. The gold standard for this purpose is CT scan and also gets its popularity. The limitation of this technique is also well recognized, mainly in terms of infavorite cost-effectiveness. It exposes the patients to radation and is not feasible to continuously assess lung areation intraoperatively. However, titration of FiO2 to obtain the optimal PEEP possesses more advantages, including directly measuring oxygenation status, ease of adjusting the PEEP according to the requirement at the given stage of the surgery, and suitable for nearly any surgery as long as the patient is under general anesthesia and with tracheal intubation; and more importantly, no extra-cost beside routine care. The disadvantage we encountered was that it took about 20 to 30 minutes to obtain the optimal PEEP and required lung recruiting. However, PEEP titration can be achieved parallel to the surgical process and does not require extra time. In addition, intraoperative atelectasis can be efficiently overcome by applying continuous PEEP without recruiting maneuvers. The titration process seems complicated, however, the process can be easily performed using modern ventilators. Therefore, obtaining and maintaining optimal PEEP could be automated in future ventilator designs”

 

Comment 4: Justification for the sample size should be provided, including assumptions, power analysis, and relevance to detecting meaningful clinical differences.

Response: Thank you for pointing out the need for a more detailed justification of the sample size calculation. This is a critical aspect of the methodology. In the revised manuscript, we have significantly expanded the “statistical analysis” section as “A previous study in the comparable patient population and for the same surgery showed that the median optimal PEEPEIT was 14 cm H2O. We assumed that a difference in PEEP levels between the two titration methods greater than 2 cmH₂O would be clinically significant, the SD of each arm was assumed to be 3 cm H2O with an α error of 0.05 and a power of 80%, at least 35 subjects were needed for each group. Considering a dropout rate of 28% based on our pilot study, 96 patients (n=48 in each group at a ratio of 1:1) were enrolled in our study” on page 5.

 

Comment 5: Potential sources of bias should be addressed, including selection, measurement, and analysis biases that may influence study outcomes significantly.

Response: We appreciate the reviewer’s constructive comment. We have carefully addressed the potential sources of bias in “Statistical analysis” section of the revised manuscript on page 5, including selection bias, measurement bias, and analysis bias that may significantly influence the study outcomes. For selection bias, we adopted randomization method by MinimPy2 software and Patients were stratified by age (<65 vs. ≥65 years) and BMI (<25 vs.≥25 kg·m –2) to test differences in age and BMI distribution. For measurement bias, and analysis bias, we adopted double blind method, all evaluators and patiehts were blinded to the group allocation.

 

Comment 6: Applicability to broader patient groups should be clarified, especially regarding different risk profiles, comorbidities, and clinical settings beyond study population.

Response: We appreciate the reviewer’s valuable comment. We have explicitly discussed the potential limitations in extending our conclusions to patients with different risk profiles, various comorbidities, and diverse clinical settings beyond our study cohort, and added corresponding explanations in the “Discussion” section on page 12-13. The revisions have been highlighted for easy identification.

 

Comment 7: Key clinical outcomes should be more clearly defined, including their measurement methods, timing, and relevance to patient-centered care and practice.

Response: We appreciate the reviewer’s insightful comment. In the “outcome measurements” section of the revised manuscript on page 4-5, we have more clearly defined all key clinical outcomes, with detailed specifications on their measurement methods, assessment time points, and clinical relevance to patient-centered care and real-world practice. Corresponding revisions have been made in the methods sections and highlighted for identification.

 

Comment 8: Future research directions should be explicitly proposed, focusing on validation studies, diverse populations, and long-term clinical outcomes assessment.

Response: We appreciate the reviewer’s valuable suggestion. In the revised manuscript on page 13, we have added “Future studies involving larger and more diverse populations are warranted to evaluate long-term clinical outcomes of this technique, such as PPCs”.

 

Comment 9: Additional sections should be considered for better structure, such as expanded discussion, methodological clarification, or enhanced background context for readers.

Response: We appreciate the reviewer’s constructive comment regarding the manuscript structure. To improve the clarity, completeness, and readability of the manuscript, we have carefully considered and added additional sections as suggested.

• To provide a more comprehensive background context, we have added details about the current research status, existing gaps, and the practical significance of addressing these gaps in “Introduction” section.
• For methodological clarification，we have added the manuscript with a detailed description of EIT applications and the underlying principle of EIT-guided PEEP titration, aiming to provide readers with a more comprehensive understanding of EIT utilization in this study on page 4.
• We also expanded potential limitations in the “Discussion” section on page 12-13.

 

Comment 10: Important findings should be explained in greater depth, emphasizing underlying mechanisms, clinical implications, and consistency with previous related studies.

Response: We greatly appreciate the reviewer’s valuable suggestion to further elaborate on our important findings. In response to this comment, we have deepened the explanation the clinical implications , consistency and discrepancies between our findings and those reported in previous related studies of the key results in the “Discussion“ section of the revised manuscript.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

to the authors of bioengineering-4187940

Thank you for taking the time and effort to incorporate our remarks into your work. I believe this review is thorough, and all of the points have been met most sincerely and efficiently.
In my opinion, this article is suitable for publication. Congratulations on your findings
Kind regards and good luck with your endeavors

Reviewer 3 Report

Comments and Suggestions for Authors

Thanks to authors for implementation the manuscript