Early detection of complications in pancreas transplants by microdialysis catheters, an observational feasibility study

Gisle Kjøsen; Kristina Rydenfelt; Rune Horneland; Einar Martin Aandahl; Pål-Dag Line; Eric Dorenberg; Audun Elnæs Berstad; Knut Brabrand; Gaute Hagen; Sören Erik Pischke; Gisli Björn Bergmann; Espen Nordheim; Trond Geir Jenssen; Tor Inge Tønnessen; Håkon Haugaa

doi:10.1371/journal.pone.0247615

Peer Review History

Original SubmissionAugust 28, 2020
29 Dec 2020 Decision Letter - Jan H.N. Lindeman, Editor PONE-D-20-26801 Early detection of complications in pancreas transplants by microdialysis catheters, an observational feasibility study. PLOS ONE Dear Dr. Kjøsen, 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. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: A single group feasibility study was conducted to detect early complications in pancreas transplants (n=34) by monitoring glucose, lactate, pyruvate, and glycerol levels every 1-2 hours post transplant. The median lactate in these patients was significantly higher in both catheters compared to non-events (n=15). The statistical methods were clearly written. Minor revisions: 1- Line 156: Indicate the statistical testing method which achieves 80% power. 2- Express p-values more precisely, rather than p>0.05. Reviewer #2: - In methods, line 126: It is not clear when the second measurement is performed. Please specify. - In methods, line 132: What was the imaging protocol before the ninth patient in the study? - In results, line 196: It would be interesting to know when the loss of functional sampling occurred. - In results: Was there any complication related to microdyalisis catheters placement? - In discussion: It could be interesting to discuss whether one determination is enough to indicate CT to gain time in thrombus diagnosis. - In discussion: It could be interesting to know if there were differences in donor characteristics between groups. ****** 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. 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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. https://doi.org/10.1371/journal.pone.0247615.r001
Revision 1
3 Feb 2021 Author Response Dear Dr. Lindeman Thank you so much for your invitation to resubmit our manuscript. We wish to thank both you, and the reviewers for your time, and for the generous and invaluable feedback. We have edited the manuscript to address the questions and concerns raised. Below, we will address each question separately. Apart from the points made by the reviewers I would appreciate if your would address the following points: firstly, the trial registration number provided in the manuscript concerns a different study protocol, secondly it would be helpful if to the readers if the reason for early termination in mentioned in the study, finally I am missing a possible sampling delay which obviously involved the dead-volume of the system and the volume required for the analyses. Unfortunately, this detail was not presented clearly in the original manuscript. The trial registration number is indeed the correct one. The submitted manuscript is however, a substudy of a larger one pertaining to pancreas transplants (The Norwegian Pancreas Transplantation (PTx) Study. The details regarding the microdialysis part can be found on clinicaltrials.gov (NCT01957696), under “other outcome measures”, #6 and #7. Changes made accordingly in manuscript pg. 4, lines 94-95. Thank you for allowing us to clarify the reason for the early termination of the study. As stated in the manuscript, the study was terminated prematurely due to an unforeseen increase in the incidence of thrombi. Our pre-study incidence was around 10%, and by the time of termination this number was 26%. There are several possible explanations for this, of which study bias is the most obvious. We actively tried to find thrombi by close monitoring with microdialysis and routine CT scans. Some of the thrombi were located to the distal splenic vein, these are thrombi that usually does not require any intervention. Most likely, some thrombi would also have gone unnoticed without a CT scan. The catheters are not likely to be the cause. Our research group have used microdialysis in a variety of settings and have implanted hundreds of these catheters without complications. In this paper the catheters were also external to the pancreatic graft, which makes it challenging to understand physiologically, how this could lead to thrombi in the graft itself. Changes made accordingly in manuscript pg. 20, lines 396-401. There is unarguably a sampling delay in the microdialysis setup. According to the manufacturer the membrane-to-collection delay is approximately 8 minutes at a rate of 1 µL/min. The analysis itself takes about 10 minutes to complete. Therefore, the total delay is about 18 minutes. In the presence of a venous thrombus, we feel this delay is not the decisive factor in terms of outcome. Changes made accordingly in manuscript pgs. 5-6, lines 125-126 Reviewer #1: Minor revisions: 1- Line 156: Indicate the statistical testing method which achieves 80% power. Thank you for alerting us to this detail which escaped the manuscript. For sample size calculation, we used Power Analysis (A& X Analytics LLC, Boston, MA) adjusted for later test with an unpaired two sample two tail t-test. We have added this sentence to the manuscript and the information about the parameters of the power calculation, pg. 7, lines 160-165. 2- Express p-values more precisely, rather than p>0.05. Thank you, there was one p-value that “fell through” the read-through. It has now been corrected to the exact p-value of 0.26. Changes made accordingly in manuscript pg. 16, line 284. Reviewer #2: - In methods, line 126: It is not clear when the second measurement is performed. Please specify. The repeat measurement was done 30 minutes later. The choice of performing a second measurement was to lessen the likelihood of the elevation representing a spurious measurement. Changes made accordingly in manuscript pg. 6, lines 131-132. - In methods, line 132: What was the imaging protocol before the ninth patient in the study? Before the ninth patient, the only mandatory radiological imaging, was an ultrasound performed within four hours after reperfusion. CT scan was only performed if the ultrasonographic images was of inadequate quality for determining arterial and venous flow. Changes made accordingly in manuscript pg. 6, lines 136-137. - In results, line 196: It would be interesting to know when the loss of functional sampling occurred. The 17 catheters that ceased functioning, had a median catheter life of 5,5 days for the anterior catheter (IQR 4-7, range 1-13), and 5 days for the posterior catheter (IQR 3.8-6.5, range 1-13). In our opinion, this range gives a “practical” approach to describe the catheter lifetime. The loss of functional sampling is most likely due to clogging of the microdialysis membrane by the protein rich exudate found surrounding pancreas grafts. Changes made accordingly in manuscript pg. 11, lines 205-207. - In results: Was there any complication related to microdyalisis catheters placement? Thank you for allowing us to address this question. We have after more than a decade and several hundreds of microdialysis catheters placed, yet to encounter significant complications both upon insertion and removal. In these 34 patients there were no complications on insertion whatsoever. Changes made accordingly in manuscript pg. 11, lines 207-208. - In discussion: It could be interesting to discuss whether one determination is enough to indicate CT to gain time in thrombus diagnosis. The microdialysis method, like any method of measurement is inherently associated with margins of error, false positives, and negatives. Despite calibration and quality controls, outliers of measurements still occur. A false positive test would, in the instance of a single determination cut off, lead to a great number of repeat CT scans. Aside from the cost and other logistical factors, this would mean a significant risk exposure both in terms of radiation, and that of nephrotoxic contrasting agents necessary for adequate imaging of the pancreatic vessels. In this study, 18/32 transplantations were by means of simultaneous pancreas kidney transplantation. In most other countries this ratio is towards 3 in 4, or higher. Using nephrotoxic contrasting agents in this group, as with any examination, should be restricted to cases where the benefit of the examination outweighs the risk. The one pretest modifier we can employ here to aid in this selection, is to minimize the false positives. In this instance, repeating the measurement. Yes, the time to diagnosis might be somewhat shortened by relying on one determination, but not without imposing a significant increased risk to the patient. We have added a paragraph in the discussion, pg. 20, lines 385-395. - In discussion: It could be interesting to know if there were differences in donor characteristics between groups. There were indeed some differences in the characteristics of the subpopulations. With three pathological cohorts and one control group, we performed a subgroup analysis. This revealed a statistically significant lower total arterial pancreatic blood flow, and a shorter cold ischaemia time in the thrombus group versus the reference cohort. Identical differences were found between the haematoma group versus the reference cohort. In the discussion of the revised manuscript (pgs. 18-19, lines 350-367), we have posed hypotheses for the possible explanations for these findings. However, the event subgroups were small in size, and care should be exercised in drawing conclusions based solely on these data. Again, we would like to thank the editor and referees for their review and evaluation. We have tried to address all the concerns raised in an adequate manner, and believe that by answering these, the manuscript has improved considerably. We would however be happy to make further corrections if this is necessary. We look forward to hearing back from you soon. Sincerely, Gisle Kjøsen, MD Consultant Anaesthesiologist Department of Emergencies and Critical Care Medicine Oslo University Hospital, Rikshospitalet Norway Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0247615.r002
10 Feb 2021 Decision Letter - Jan H.N. Lindeman, Editor Early detection of complications in pancreas transplants by microdialysis catheters, an observational feasibility study. PONE-D-20-26801R1 Dear Dr. Kjøsen, 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, Jan H.N. Lindeman Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0247615.r003
Formally Accepted
15 Feb 2021 Acceptance Letter - Jan H.N. Lindeman, Editor PONE-D-20-26801R1 Early detection of complications in pancreas transplants by microdialysis catheters, an observational feasibility study. Dear Dr. Kjøsen: 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. Jan H.N. Lindeman Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0247615.r004

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