It’s Getting Hot in There: In Vitro Study on Ureteral Tissue Thermal Profiles During Laser Ureteral Lithotripsy
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
Abstract
The abstract is concise. All the necessary information about the study is included.
Introduction
-The information provided in this section is valuable for the comprehension of the manuscript.
-The pathophysiology behind ureteral strictures is well explained.
- The objective of the study is mentioned in the last paragraph.
Methods
-The study design is well explained.
-The experimental set-up is clearly analyzed.
-If no ureteral tissue was used, maybe the experimental set up should be altered to in vitro.
-Were the stones artificial or retrieved after surgery of real cases ?
-Could manual pump irrigation be used for this experimental study? Maybe this would replicate more accurately real life cases.
Results
-The results are presented in an extensive way.
-The tables are really helpful and necessary for the completion of the authors' work.
-The thermal profiles presented are logical based on the power settings used and the diameter of the fiber in comparison to that of the working channel of the ureteroscopes.
-In everyday practice, it is uncommon to prolong the activation time more than 10 seconds, due to visibility distortion and the danger of thermal damage. Nevertheless, it is interesting to observe the thermal patterns beyond that point.
Discussion
- The discussion is of good quality and includes updated data.
-The presentation of similar studies and the discussion of the findings could be extended.
-The authors should inform extensively the reader about the study's limitations.
Conclusion
From the presented data, the conclusion is complete and represents the work that the authors did.
Author Response
Comment 1:
-If no ureteral tissue was used, maybe the experimental set up should be altered to in vitro.
-Were the stones artificial or retrieved after surgery of real cases?
-Could manual pump irrigation be used for this experimental study? Maybe this would replicate more accurately real life cases.
Response 1:
Thank you for the comments.
- This experiment was conducted under controlled laboratory conditions using a ligated PTFE tube segment to simulate the human ureter. As such, this setup is suitable for an ex vivo study conducted outside of a living organism (explained in Material and Method, page 3, line 80).
-The stones used in this study were artificial carbonate apatite stones with 1000 Hounsfield Units. The author has clarified the statement on page 3, lines 83-84.
-Most of our local centers use a hand pump or irrigation bag height during ureteroscopy, thus this experiment is trying to replicate our real-life practices. In this experiment, we keep the irrigation flow rate as standard to focus on the other factors affecting the outcome. The statement on irrigation flow rate is recorded in the manuscript (Page 2, lines 76).
Comment 2: The authors should inform extensively the reader about the study's limitations.
Response 2: Thank you, Reviewer, the limitations of the study have been added in the last paragraph of the discussion part (page 8, lines 237-246).
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for Authors
The manuscript presents an interesting ex vivo study investigating the thermal profile of ureteral tissue during laser lithotripsy. The topic is relevant to urological practice, as thermal injury is a known complication of this procedure. The study design is straightforward, and the results are clearly presented. However, there are several areas where the manuscript could be improved.
- Novelty: The study's main finding, that temperature increases with laser power and duration, is not particularly novel.This relationship is well-established in the literature. The authors should more clearly articulate the unique contribution of their study, perhaps by emphasizing the specific power settings and fiber sizes tested or the practical implications for clinical practice.
- Clinical Relevance: The clinical relevance of the findings could be better emphasized. While the study demonstrates temperature increases, it does not directly link these increases to tissue damage or clinical outcomes. The authors could discuss the implications of their findings for laser lithotripsy settings and techniques, potentially offering recommendations for minimizing thermal injury.
- Introduction: The introduction could be more concise and focused. Some of the information presented is not directly relevant to the study's research question.
- Methods: The methods section could be more detailed. For example, the authors could provide more information on the type of holmium laser used, the irrigation fluid, and the temperature measurement technique.
- Statistical Analysis: The statistical analysis could be more robust. The authors use ANOVA and Duncan's post hoc tests,but they do not report effect sizes or confidence intervals. These additional statistics would provide a more complete picture of the magnitude and significance of the observed differences.
- Figures: The figures could be improved. Figure 1 is difficult to interpret, and Figure 3 is not clearly explained in the text.
- Discussion: The discussion could be expanded to include a more thorough comparison with previous studies. The authors cite several relevant papers but do not always fully integrate their findings into the discussion. A more in-depth analysis of how the current study's results compare and contrast with previous work would strengthen the manuscript.
- Language: The manuscript would benefit from a thorough language edit to improve clarity and conciseness.
- I recommend that the authors revise the manuscript to address the concerns raised above. With these revisions, the manuscript could be a valuable contribution to the literature on laser lithotripsy.
Comments on the Quality of English Language
The manuscript would benefit from a thorough language edit to improve clarity and conciseness.
Author Response
Comment 1: Novelty: The study's main finding, that temperature increases with laser power and duration, is not particularly novel. This relationship is well-established in the literature. The authors should more clearly articulate the unique contribution of their study, perhaps by emphasizing the specific power settings and fiber sizes tested or the practical implications for clinical practice.
Response 1: Thank you for the comments. Apart from the power setting and duration, the author is trying to study the component that contributes to laser power, which is the frequency and energy. At the same power setting which component affects the temperature more. The unique part of the study is the utilization of different laser fibre sizes with varying sizes of ureteroscope to study the outcome difference using different scope and fibre combinations.
Comment 2: Clinical Relevance: The clinical relevance of the findings could be better emphasized. While the study demonstrates temperature increases, it does not directly link these increases to tissue damage or clinical outcomes. The authors could discuss the implications of their findings for laser lithotripsy settings and techniques, potentially offering recommendations for minimizing thermal injury.
Response 2: In this study, the author uses the temperature of 43°c as the threshold temperature causing cell damage, which is extensively studied in multiple in-vitro models which is quoted in the author’s recommendation. Although these studies mainly focus on the effect of hyperthermia in chemotherapeutic agents, the author believes that cellular response to hyperthermia can also be utilized in ureteral tissue. Other research on factors causing ureteral stricture also included the use of laser lithotripsy which causes a rise in intraureteral temperature during lithotripsy.
Comment 3: Introduction: The introduction could be more concise and focused. Some of the information presented is not directly relevant to the study's research question.
Response 3: Thank you reviewer. The introduction has been edited based on your advice (Page 2).
Comment 4: Methods: The methods section could be more detailed. For example, the authors could provide more information on the type of holmium laser used, the irrigation fluid, and the temperature measurement technique.
Response 4: Thank you reviewer, the information is on page 2 (lines 73-76) explaining the temperature of irrigation fluid at 37 °C using a fluid warmer, ureter internal diameter at 7 mm, and rate of irrigation fluid at 15 mL / min (by keeping the saline bag height at 100 cm H20). The type of holmium laser is explained on Page 3, line 94. The temperature measurement technique is explained on page 3, lines 89-92.
Comment 5: Statistical Analysis: The statistical analysis could be more robust. The authors use ANOVA and Duncan's post hoc tests, but they do not report effect sizes or confidence intervals. These additional statistics would provide a more complete picture of the magnitude and significance of the observed differences.
Response 5: Thank you Reviewer, information has been added to the text in Page 3, lines 109-110.
Comment 6: Figures: The figures could be improved. Figure 1 is difficult to interpret, and Figure 3 is not clearly explained in the text.
Response 6: Thank you Reviewer. Intensive explanation on Figures have been added and revised (Page 6-7, lines 164-186).
Comment 7: Discussion: The discussion could be expanded to include a more thorough comparison with previous studies. The authors cite several relevant papers but do not always fully integrate their findings into the discussion. A more in-depth analysis of how the current study's results compare and contrast with previous work would strengthen the manuscript.
Response 7: Thank you reviewer. Based on your advice, the discussion session has been edited (Page 8, lines 218-252).
Comment 8: Language: The manuscript would benefit from a thorough language edit to improve clarity and conciseness.
Response 8: Thank you for the comments. We have revised thoroughly on the grammar and language edit.
Comment 7:
Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for Authors
It is a study evaluating the thermal effect of different laser settings in combination with different sizes of ureteroscopes and laser fibers in an ex-vivo model.
The study is well-written, however, there are major concerns about the study design.
1) Is there any literature on the efficacy of this ex-vivo model? Are there any references to it?
2) The PTFE tube cannot simulate adequately the human ureter. Additionally, the ligated end cannot simulate the compliance of the renal pelvic.
3) Ureteral sheath may have an important impact on the temperature. Unfortunately, this variable was not investigated.
Comments on the Quality of English Language
As above
Author Response
Comment 1: Is there any literature on the efficacy of this ex-vivo model? Are there any references to it?
Response 1: There is a similar study by Liang et al on the thermal effect of holmium laser during ureteroscopic lithotripsy, which was published in BMC Urology (https://doi.org/10.1186/s12894-020-00639-w). To date, there is no similar study that is carried out on real patients or in-vitro animal model.
Comment 2: The PTFE tube cannot simulate adequately the human ureter. Additionally, the ligated end cannot simulate the compliance of the renal pelvic.
Response 2:
This is indeed one of the limitations of this ex-vivo study as real patients will have other factors that affect the outcome temperature, such as human homeostasis and ureteral blood flow that helps carry away the heat. This is difficult to simulate in an ex-vivo model.
One of the PTFE tubes is ligated at one end to simulate the situation of impacted stone, in which there is minimal or nil water flow proximal to the site of impaction. This condition will cause a higher temperature rise during lithotripsy, which leads to stricture. This study aims to study the methods to reduce this complication in such clinical scenarios.
However, it is true that in the case of partial obstruction, the compliance of the renal pelvis and the water flow surrounding the stone will indeed affect the outcome temperature.
Comment 3: Ureteral sheath may have an important impact on the temperature. Unfortunately, this variable was not investigated.
Response 3: The author is simulating lithotripsy in a straight ureter. In our local daily practice, we do not routinely use a ureteral sheath in lithotripsy of ureteral stones.
Author Response File: Author Response.pdf
Reviewer 4 Report
Comments and Suggestions for Authors
The authors have designed an ex-vivo ureteral model with temperature sensor to assess temperature changes with various laser fibers sizes 272 vs 365, ureteroscopes 6f vs 7f, various power settings (frequency 5 to 25Hz, energy 0.2 -3.0J) and activation durations (3s, 5s, 10s, 15s, 20s, 25s, 30s).
Interesting there was no difference between URS size. One would think the smaller diameter ureteroscope would allow for better irrigation circulation and lower temperature.
The 365 micron laser had significantly higher temperature than the 272 micron at longer durations. Why is that? I assumed you were using identical power for the two fibers size comparison?
It was not clear in the methodology but the 1cm stone introduced, was this lasered? If so, how did you control for effects of the stone breaking/shorting of laser fiber (ie wear and tear on tip).
You suggested in your introduction higher power and higher frequency trend of laser is an important variable in successful lithotripsy. Was there an energy setting/variable point where maximal stone fragmentation is achieved and anything beyond this point was moot.
Can you reformat table 1 to present data clearer? Difficult to understand which results are significant. Maybe using bold text.
How does fluid irrigation temperature impact your study? Real life, we do not use irrigation at body temperature. Usually it is room temperature which much lower.
Also, there will be heat sink effect due to blood vessels, bowel, muscle, other organs which are adjacent to the ureter which would dissipate heat as well.
Comments on the Quality of English Language
Your manuscript needs significant editing as well ie grammar, word choice etc.
Author Response
Comment 1: Interesting there was no difference between URS size. One would think the smaller diameter ureteroscope would allow for better irrigation circulation and lower temperature.
Response 1: This is one of the contributing conclusions from this study. The two distinct sizes of the ureteroscope experienced a rise in temperature upon the initiation of laser activation. However, both sizes of the ureteroscopes did not reach the threshold temperature.
Comment 2: The 365 micron laser had significantly higher temperature than the 272 micron at longer durations. Why is that? I assumed you were using identical power for the two fibers size comparison?
Response 2: The larger laser fiber and smaller fibre are compared at the same power setting. The postulation of the higher temperature rise in larger fibre is discussed in the discussion. The author postulates that larger-diameter fibers have a higher capacity to deliver laser energy, and larger-diameter fibers may have less efficient heat dissipation compared to smaller ones. Another reason is that the use of larger fiber in the ureteroscope's working channel decreased the irrigation flow rate, consequently hindering the heat exchange process. The detailed postulation of this is explained in the discussion.
Comment 3: It was not clear in the methodology but the 1cm stone introduced, was this lasered? If so, how did you control for effects of the stone breaking/shorting of laser fiber (ie wear and tear on tip).
Response 3:
Yes, the stone was lasered, simulating the real-life clinical practice on real patients.
The laser tip was trimmed after each set of 30 seconds of laser activation. However, the exact method to control the wear and tear on the tip is not included. And the length of fiber to it’s outer coating is also not measured.
The operator of laser lithotripsy is maintained at single same operator throughout the experiment. Laser firing is aimed towards the center of the stone, and the stone is changed to a new stone after a lumen on the stone is seen, as to minimize the change in irrigation flow when there is flow proximal to the stone. Undeniably, there will be minimal variation in the pattern of lithotripsy with repetitive activation and different anatomy of stone.
Comment 4: You suggested in your introduction higher power and higher frequency trend of laser is an important variable in successful lithotripsy. Was there an energy setting/variable point where maximal stone fragmentation is achieved and anything beyond this point was moot.
Response 4:
The author focused on the temperature rise during laser lithotripsy, and the stone is changed to a new stone after a lumen on the stone is seen, to minimize the change in irrigation flow when there is flow proximal to the stone.
There is thus no result on the energy setting/variable point where maximal stone fragmentation is achieved.
Comment 5: Can you reformat table 1 to present data clearer? Difficult to understand which results are significant. Maybe using bold text.
Response 5: Thank you Reviewer, we have revised Table 1 into figures to improve the pattern of thermal changes at different factors. Hopefully, the figures will make it easier to interpret the findings.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for Authors
Dear authors,
Ex vivo can be characterized an experiment that is conducted in or on tissues obtained from an organism and maintained under optimum conditions mimicking the natural condition. In this experimental study, no cells or ureteral tissue were obtained. My suggestion would be to reconsider the in vitro renaming of your set-up.
In addition, the authors should comment and underline the superiority of manual pump irrigation regarding the thermal effect on the renal tissue in the discussion section.
Nevertheless, the quality of the manuscript has been improved after the first revision. Some of the issues and questions have been addressed.
Author Response
Comment 1 :
In vitro can be characterized an experiment that is conducted in or on tissues obtained from an organism and maintained under optimum conditions mimicking the natural condition. In this experimental study, no cells or ureteral tissue were obtained. My suggestion would be to reconsider the in vitro renaming of your set-up.
Author Responses 1 :
Noted with thanks on the correction. Authors agreed on the explanation and will edit and rename the set-up to in vitro experiment.
Comment 2:
In addition, the authors should comment and underline the superiority of manual pump irrigation regarding the thermal effect on the renal tissue in the discussion section.
Author Responses 2:
Manual pump irrigation is superior as it is a more accurate and more controlled method to ensure the constant flow rate of saline during ureteroscopy.
Unfortunately, not all of the centre in my country has the pump irrigation, thus we still use the irrigation height of saline bag with or without a bulb irrigator(eg Pathfinder) to control the irrigation flow.
In a paper by Felipe Pauchard in ‘A Practical Guide for Intra-Renal Temperature and Pressure Management during Rirs: What Is the Evidence Telling Us’, he presented a table on the effect of saline bag height to irrigation flow and the safe laser power setting. We thus used this formula in the centre without the manual pump irrigation machine.
This is thus one of the limitation of this study, and I’ve added on in the discussion section based on reviewer’s comment.
Citation: Pauchard, F.; Ventimiglia,E.; Corrales, M.; Traxer, O. A Practical Guide for Intra-Renal Temperature and Pressure Management during Rirs: What Is the Evidence Telling Us. J. Clin. Med. 2022, 11, 3429. https:// doi.org/10.3390/jcm11123429
Comment 3:
Nevertheless, the quality of the manuscript has been improved after the first revision. Some of the issues and questions have been addressed.
Author Responses 3:
Thank you for the valuable comments.
Author Response File: Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for Authors
The revised manuscript titled "It's Getting Hot in There: Ex Vivo Study on Ureteral Tissue Thermal Profiles During Laser Ureteral Lithotripsy" presents an improved and more comprehensive investigation into the thermal dynamics associated with laser lithotripsy in the context of ureteroscopic procedures. The authors have successfully addressed several key points raised in the previous review, significantly enhancing the overall quality and clarity of the manuscript. The inclusion of the statistical analysis methodology and expanded discussion significantly strengthens the manuscript's scientific rigor and provides a more nuanced interpretation of the findings. The authors have also meticulously refined the language and presentation, making the manuscript more accessible and engaging for a broader readership. The revised manuscript represents a valuable contribution to the field of urology, offering insights into the thermal implications of laser lithotripsy and providing practical guidance for optimizing clinical practice. The improvements made in this revision demonstrate the authors' commitment to scientific excellence and their responsiveness to constructive feedback. In its current form, the manuscript is well-suited for publication and is likely to be of significant interest to clinicians and researchers alike.
Author Response
Comment 1 :
Thermal Profiles During Laser Ureteral Lithotripsy" presents an improved and more comprehensive investigation into the thermal dynamics associated with laser lithotripsy in the context of ureteroscopic procedures. The authors have successfully addressed several key points raised in the previous review, significantly enhancing the overall quality and clarity of the manuscript. The inclusion of the statistical analysis methodology and expanded discussion significantly strengthens the manuscript's scientific rigor and provides a more nuanced interpretation of the findings. The authors have also meticulously refined the language and presentation, making the manuscript more accessible and engaging for a broader readership. The revised manuscript represents a valuable contribution to the field of urology, offering insights into the thermal implications of laser lithotripsy and providing practical guidance for optimizing clinical practice. The improvements made in this revision demonstrate the authors' commitment to scientific excellence and their responsiveness to constructive feedback. In its current form, the manuscript is well-suited for publication and is likely to be of significant interest to clinicians and researchers alike.
Author Response 1:
Thank you for your valuable comments and the authors are thankful for the positive comments given. No further changes were made in the manuscript.
