Implantation of a Vascular Access Button for Chronic Blood Sampling and Drug Administration in the Rabbit
Round 1
Reviewer 1 Report
This is a nice paper. However, I have some comments. The findings from this paper are excellent and worthy to review. This manuscript contained some questions described below. I think this paper is interesting, this review contributes to future's clinical medicine largely. I have some questions from a point of view of clinical medicine. I found the construction of the blood collection port described in this paper to be a very useful and innovative method. However, I think there are some problems with the creation of this port. Please let me know if this affects the reliability of the data as experimental data. For example, I assume that anticoagulants may be used to maintain the port, and abnormal values may appear when blood tests for coagulation function are performed. Please let me know how this is overcome. I have a concern that an elevated inflammatory response due to increased cytokines associated with the surgical procedure and vascular injury in the setting of vascular surgery with an implanted prosthesis could also be a potential bias when obtaining experimental data samples. If this port should malfunction during the course of the experiment, e.g., thrombus occlusion in the port, please let me know how the subsequent blood draw will be performed. What do you think would be the impact on the experimental data if you were to collect blood in a different manner?
Author Response
Dear Reviewer,
Thank you for your time in reviewing our manuscript! I greatly appreciate your interest in the implant and the functionality, especially while on study. Hopefully, I addressed your questions adequately below. If not, please do not hesitate to follow up with me.
Jon
For example, I assume that anticoagulants may be used to maintain the port, and abnormal values may appear when blood tests for coagulation function are performed. Please let me know how this is overcome. - Correct, citrate is used as anticoagulant/lock in between studies. While on study, the system is flushed free of anticoagulants prior to sampling. Additionally, a "dirty sample" is collected prior to a study sample to ensure it is from circulating blood. I have a concern that an elevated inflammatory response due to increased cytokines associated with the surgical procedure and vascular injury in the setting of vascular surgery with an implanted prosthesis could also be a potential bias when obtaining experimental data samples. - Again, you are correct in that an inflammatory response will be present while the animal recovers from surgery. Therefore, all implanted animals are allowed 2 - 4 weeks to fully heal and return to baseline/normal prior to study. Additionally, baseline blood work is collected prior to study, if abnormalities are present then the animal is not used. If this port should malfunction during the course of the experiment, e.g., thrombus occlusion in the port, please let me know how the subsequent blood draw will be performed. - One of the main reasons we use a port is the reliability of the implant and ability to collect blood throughout the study. It is actually the peripheral vessels that tend to fail more often, however, if the port did fail then the sample would be collected from a peripheral vessel such as the auricular vein. What do you think would be the impact on the experimental data if you were to collect blood in a different manner? - No impact, several studies have been done comparing samples side by side from a port and a peripheral vessel.
Reviewer 2 Report
Authors evaluated the use of a vascular access button, an implant commonly used in 19 small rodents, as a refinement to the current chronic models in use in the industry. Overall, the 20 results were outstanding, and an established model was created.
Although this manuscript is potentially interesting, several issues arise.
There were a few attractive findings in this manuscript.
It is helpful that this model will be compared with another model.
Is this surgery required to be special technic, idea, method?
Authors should show this operation in abstract.
Authors should present this study attractive.
Authors should show several cases using this model.
Illustration may be helpful in this manuscript.
Author Response
Dear Reviewer,
Thank you for time and effort in reviewing our manuscript. Hopefully, I addressed your questions/concerns appropriately below.
Jon
It is helpful that this model will be compared with another model. - it is compared to two other models (exteriorized catheters and vascular access ports) in the Discussion section.
Is this surgery required to be special technic, idea, method? - the focus of the manuscript is to share the application of an implant that is commonly used in mice/rats applied to rabbits and how to surgically implant it and maintain it.
Authors should show this operation in abstract. - abstract is limited to a certain number of words thus the operation is covered in great detail in the body of the manuscript.
Authors should present this study attractive. - I am not sure what is meant by this comment?
Authors should show several cases using this model. - seventeen animals were instrumented with this model.
Illustration may be helpful in this manuscript. - detailed description was provided in the surgical procedure section therefore we did not feel an illustration was necessary.
Reviewer 3 Report
The manuscript is well-written and easy to read. My major concern is that vascular access button manufacturer was not mentioned. It would be worthy to show whole system on a figure, especially for reader who is not familiar with devices used in animals. Do you publish your experience with ports in rabbits? Is there any literature related suboptimal outcome of ports? Please cite it. Are VABs designed for rabbits or it is offlabel use, please comment.
Author Response
Dear Reviewer,
Thank you for your time and effort in reviewing our manuscript! I addressed your questions below. Please let me know if you have any follow up questions or suggestions.
Sincerely,
Jon
My major concern is that vascular access button manufacturer was not mentioned. - Excellent catch, I did not realize a description of the implant was missing! I added it to the manuscript. It would be worthy to show whole system on a figure, especially for reader who is not familiar with devices used in animals. - Great suggestion, a picture of the implant was added. Do you publish your experience with ports in rabbits? - We have not, just discuss it in this manuscript. Is there any literature related suboptimal outcome of ports? - None that I was able to find in rabbits. There is a ton of literature in NHPs and canines. Please cite it. Are VABs designed for rabbits or it is offlabel use, please comment. - VABs were designed for small rodents such as mice and rats, thus why we are excited to share our experience with them in rabbits!
Reviewer 4 Report
The authors evaluated the use of a vascular access button, an implant commonly used in small rodents, as a refinement to the current chronic models in use in the industry. They proposed to use original vascular access button in rabbits for routine PK studies. The manuscript is well organized and has a logical structure. The figures and tables are legible and clear. The conclusive part seems to show impressive issues for readers. I would like to congratulate the authors on the the study. However, I would like to put forward some comment to discuss.
1. The magnetic protective cap semms to be another key pint for safety ebaluation. Please, extend a discussion about it in the section "Discussion".
2. It would be great to see an evaluation of risks of bleeding and bacterial contaminations. Could the authors provide this information ?
Author Response
Dear Reviewer,
Thank you for the comments on our manuscript, your time is greatly appreciated! Please see below for answers to your questions.
Thanks,
Jon
1. The magnetic protective cap semms to be another key pint for safety ebaluation. Please, extend a discussion about it in the section "Discussion". -The protective cap is discussed several times in both the Methods and Discussion sections. Is there a specific topic regarding the cap you feel should be discussed?
2. It would be great to see an evaluation of risks of bleeding and bacterial contaminations. Could the authors provide this information ? - We are extremely pleased by how well the rabbits do with these implants and to date, we have not seen a bacterial infection. This is why following strict aseptic technique is extremely important when working with a vascular implant. Additionally, there is no risk of bleeding unless the catheter was not properly attached to the implant, however, that would be quite evident at the time of surgery and easily corrected.
Reviewer 5 Report
In this manuscript Ehrmann et al describe an elegant and very useful new method for chronic blood sampling in rabbits. This methods is an innovative improvement in animals work and will reduce the animal stress during blood sampling, and therefor fits to the 3R strategies in animal work.
I just have two minor comments:
Please provide more detailed information on the buttons used in this procedure. As they are a crucial element in the set-up, more information is essential ( are they commercially available ? if yes , where? how do they look like, composed ?) that info would help to implement this elegant model elsewhere too.
What about sepsis in relation to the button implants? As the authors report sepsis a one of the major problems in the alternatives approaches like catheter placement, it would be good to discuss the (lack of) sepsis appearance in the animals receiving the button in one or two paragraphs. This might point out one of the strong beneficial points of this elegant new method
Author Response
Dear reviewer,
Thank you for your review of our manuscript! We greatly appreciate your time and effort. Please see our responses below to your questions.
Sincerely,
Jon
Please provide more detailed information on the buttons used in this procedure. As they are a crucial element in the set-up, more information is essential ( are they commercially available ? if yes , where? how do they look like, composed ?) that info would help to implement this elegant model elsewhere too. - Excellent point, also suggested by another reviewer. This information and a picture will be added to the manuscript.
What about sepsis in relation to the button implants? As the authors report sepsis a one of the major problems in the alternatives approaches like catheter placement, it would be good to discuss the (lack of) sepsis appearance in the animals receiving the button in one or two paragraphs. This might point out one of the strong beneficial points of this elegant new method - The lack of sepsis has been a very nice benefit of this implant leading to a chronic model! Following strict aseptic technique when working with the implant is the key to success. A few additional discussion points were added to the manuscript to highlight this, thank you!
Round 2
Reviewer 2 Report
Revised manuscript has not been responded to the comments from the reviewer.
Author Response
Dear reviewer,
We responded to your comments/suggestions in our responses during round 1 and asked for clarification for some of your suggestions. Additionally, the manuscript was revised in several areas. Could you please provide specific details of what changes/additions you feel are still necessary for this manuscript to move forward.
Thank you in advance!
Jon
Round 3
Reviewer 2 Report
Authors proposed an implantation of a vascular access button as excellent rabbit model for chronic blood sampling and drug administration.
Although this model may be useful and important, this abstract is not attractive or informative.
Abstract is almost introduction and discussion and has a few results.
Following information in abstract may be helpful for readers to read a main text.
How many rabbits? Success rate. How long operation time? Which vessels? How long use in this model. Did you need special technic or instrument?
Author Response
The abstract has been revised as suggested by the reviewer.
