Evaluating Opioid Dosing in COVID-19 and Non-COVID-19 ICU Patients Using Nociception Level Monitoring
, Hendrik Helmerhorst 2, Evert de Jonge 1 and Albert Dahan 2
Round 1
Reviewer 1 Report
The work is interesting because it tries to define an objective methodology to evaluate pain in sedated patients in an Intensive Care Unit (NOL). It also integrates the observations with standard methods for pain assessment and discusses this aspect appropriately.The work mainly aims to evaluate the effectiveness of the Nociception Level Monitor (NOL) in assessing pain in patients under deep sedation, also compared to other methods.
Line 61 and following. In Material and Methods section there is a methodological weakness. This exploratory observational study was performed in two phases, and patients Bispectral Index (BIS) measurements were included in the second phase. Both protocols have been officially registered, but a possible repetition of the experiment is very difficult.
The results seem to confirm the effectiveness of the NOL in measuring pain, and regarding the comparison of opioid use it seems that COVID-19 patients received more opioids than controls, but the evaluations with NOL do not demonstrate differences between the groups.
Table 3. The difference in propofol doses between the two groups could be discussed in more detail, to explain it.
In general discussion is detailed and understandable enough.
Lines 362 and following. The first and third limitations are clear. The second is not easily understandable given that the study was designed for this purpose.
The figures and tables are clear.
The references are adequate
Author Response
Dear Editor,
We are grateful for the opportunity to revise our manuscript and are pleased to hear that only minor revisions were necessary. We have carefully addressed all the comments and suggestions provided by the reviewers. We have uploaded two versions of the manuscript: one with the revisions marked in red and a clean version without revisions.
Thank you for considering our work for publication in COVID. We look forward to the final decision on the publication of our manuscript.
Kind regards,
On behalf of the co-authors,
L.I. van der Wal
Comment 1: In Material and Methods section there is a methodological weakness. This exploratory observational study was performed in two phases, and patients Bispectral Index (BIS) measurements were included in the second phase. Both protocols have been officially registered, but a possible repetition of the experiment is very difficult.
Response 1: Thank you for pointing this out. We made every effort to be as transparent as possible by registering both protocols. However, we acknowledge that the division of the study in two parts, along with the fact that the study was conducted in the COVID-19 pandemic, makes it difficult to replicate the exact conditions and approach. We have now added this as limitation in the discussion section in line 376-381: “Lastly, the time gap between the inclusion of the first and second group of 20 patients could influence outcomes due to changing COVID-19 protocols. Also, conducting the study in two phases may pose challenges in replicating the study. However, when analyzing the primary and secondary endpoints of both datasets separately, similar results were obtained, and both protocols were registered to ensure transparency and replicability.”
Comment 2: The results seem to confirm the effectiveness of the NOL in measuring pain, and regarding the comparison of opioid use it seems that COVID-19 patients received more opioids than controls, but the evaluations with NOL do not demonstrate differences between the groups.
Response 2: Thank you for your comment. Our data suggests that NOL is able to identify a painful stimulus in ICU patients. We also observed that COVID-19 patient received more opioids than controls. However, as discussed in the discussion part, we cannot conclude that these higher doses were specifically needed for pain management, as NOL values were low in both groups. Higher opioid doses may also have been administered for other reasons, such as difficulties with mechanical ventilation and the need to subdue excitation.
Comment 3: The difference in propofol doses between the two groups could be discussed in more detail, to explain it.
Response 3: Thank you for pointing this out. As mentioned in our discussion (lines 331-340), the differences in propofol dosing may be due to difficult mechanical ventilation and the need to subdue excitation. However, due to the observational nature of the study, we are unable to determine the exact reasons for the higher propofol doses, and this will remain speculative. We hope this clarifies this matter.
Comment 4: Lines 362 and following. The first and third limitations are clear. The second is not easily understandable given that the study was designed for this purpose.
Response 4: We agree that with the reviewer that the study was designed for this purpose. We have therefore removed this limitation from the discussion.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Title need to be precise and state the message clearly.
In introduction add few sentences about covid and need for analgesic treatment.
Material method should number subsections.
Was data collection blinded by investigator?
Study was conducted "between October 6, 2020, and November 11, 2021".... why then it was not published?
All over the manuscript minimise abbreviation it brake the flow to audience.
Conclusion should not look like result and able to project future research and limitation ofstudy.
NA
Author Response
Dear Editor,
We are grateful for the opportunity to revise our manuscript and are pleased to hear that only minor revisions were necessary. We have carefully addressed all the comments and suggestions provided by the reviewers. We have uploaded two versions of the manuscript: one with the revisions marked in red and a clean version without revisions.
Thank you for considering our work for publication in COVID. We look forward to the final decision on the publication of our manuscript.
Kind regards,
On behalf of the co-authors,
L.I. van der Wal
Comment 1: Title need to be precise and state the message clearly.
Response 1: Thank you for your comment. In order to make the message more clear and to meet your request we have changed the title into: “Evaluating opioid dosing in COVID-19 and non-COVID-19 ICU patients using Nociception level Monitoring”
Comment 2: In introduction add few sentences about covid and need for analgesic treatment.
Response 2: Thank you for your comment. We agree with the reviewer that an explanation of why mechanically ventilated patients require analgesia is missing in the introduction. Therefore, we have added the following sentence in line 33-35: “Apart from pain management, mechanically ventilated patients need adequate analgesia to prevent discomfort, pain, and increased respiratory effort that may by caused by and can interfere with mechanical ventilation.”
Comment 3: Material method should number subsections.
Response 3: Thank you for your comment. We have numbered the subsection of the methods.
Comment 4: Was data collection blinded by investigator?
Response 4: Due to the observational nature of this study the data collection was not blinded.
Comment 5: Study was conducted "between October 6, 2020, and November 11, 2021".... why then it was not published?
Response 5: Thank you for your question. Although the study was conducted between October 6, 2020, and November 11, 2021, the publication process was delayed due to several factors. These included the time required for data analysis, manuscript preparation, and the peer review process. Additionally, once we were ready to submit our manuscript (early 2023) a lot of journals would not accept a manuscript that concerned COVID-19 patients.
Comment 6: All over the manuscript minimize abbreviation it brake the flow to audience.
Response 6: We agree with the reviewer that excessive use of abbreviations makes the manuscript less readable. We have made an effort to limit the number of abbreviations; however, using full terms for NOL, BIS, RASS, and TWA would reduce readability, and most of these abbreviations are commonly used in the field. As we agree with the reviewer on the importance of minimizing abbreviations, we have now written “OR” as “operating room” throughout the manuscript.
Comment 7: Conclusion should not look like result and able to project future research and limitation of study
Response 7: We agree with the reviewer that our conclusion is a little bit long in summarizing our results. Therefore we have deleted the following from the conclusion: “Both groups had low NOL and BPS values with lower BIS and RASS values in the COVID-19 group, suggesting high analgesia in both groups and deeper sedation in the COVID-19 group.”
Author Response File: Author Response.pdf
