Exposure of patients to di(2-ethylhexy)phthalate (DEHP) and its metabolite MEHP during extracorporeal membrane oxygenation (ECMO) therapy

Franziska Kaestner; Frederik Seiler; Daniel Rapp; Elisabeth Eckert; Johannes Müller; Carlos Metz; Robert Bals; Hans Drexler; Philipp M. Lepper; Thomas Göen

doi:10.1371/journal.pone.0224931

Peer Review History

Original SubmissionAugust 13, 2019
25 Sep 2019 Decision Letter - Jaymie Meliker, Editor PONE-D-19-22817 Internal exposure to di(2-ethylhexyl)phthalate (DEHP) and its metabolite MEHP during extracorporeal membrane oxygenation (ECMO) therapy PLOS ONE Dear Prof. Dr. med. Lepper, 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. We would appreciate receiving your revised manuscript by Nov 09 2019 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. 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Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Interesting paper on exposure to DEHP during ECMO and other intense Medical treatment. Specific comments: 1. Title: the term Internal exposure is strange, why not Intravenous exposure, as this is what you are measuring. Or simply Exposure. 2. I miss in the article any reference to the ongoing regulatory developments, with more stringent requirements for the use of DEHP, or plasticizers in general. This must be added. 3. Page 6, line 166: not sure if accuracy is the right word here, do you mean recovery? 4. Results, page 8: lots of data points for DEHP and MEHP are shown, but several questions remain: was there a correlation between days on ECMO and the levels determined. Was there a correlation between number of red cell transfusions and exposure. In figure 2 and 3: probably there are patients with more than two cannulas and more than one membrane; worthwhile to give this information. Are these patients also having more transfusions and other Medical treatment with PVC components? 5. In table 2 it would be of value to have also the DEHP and MEHP values in the blood added. 6. Discussion, page 10, line 269: maybe better to formulate differently, high values are found to be correlated with longer and more intense ECMO (several canulas, membranes), but not in all patients. 7. Discussion, page 11 line 294 ctd. and page 12 line 317 ctd. seems to be in contrast. Line 294 is 'could be' and in line 317 it is a hypothesis. In my opinion the main reason for higher DEHP in patients without urine output is inhibited elimination, and perhaps more intense treatment plays an additional role, according to the hypothesis. 8. Discussion, page 11, line 300: please add that cell saver treatment includes a washing step. 9. Discussion, page 11, line 314 ctc: according to the individual points in the graphs, it looks like low DEHP is also low MEHP, can you add a remark on this point to the discussion in the part where you discuss MEHP proportion. 10. Introduction: although it is true that DEHP is (re)classified as carcinogenic, it has to be clear that the values needed for this effect are far above those for the endocrine disruptive effects. ****** 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. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". 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Revision 1
22 Oct 2019 Author Response Reviewer #1: Interesting paper on exposure to DEHP during ECMO and other intense Medical treatment. We thank the reviewer for his critical appraisal of our paper. We would like to answer the raised issues as follows: Specific comments: 1. Title: the term Internal exposure is strange, why not Intravenous exposure, as this is what you are measuring. Or simply Exposure. We fully agree with the reviewer and hence change the title to simply „Exposure of…“ 2. I miss in the article any reference to the ongoing regulatory developments, with more stringent requirements for the use of DEHP, or plasticizers in general. This must be added. We agree and add the following paragraph in the manuscript in line 77-82: Additionally, DEHP in much higher values is classified as a carcinogen for which a non-genotoxic mode of action is predominant (8). The application of several phthalates is regulated in the European Union and DEHP and several other phthalates are banned for the manufacturing of children's toys (9, 10). In contrast, a restriction of DEHP use in medical devices does not exist. Nevertheless, the European Scientific Committee on Emerging and Newly-Identified Health Risks recommended a substitution of DEHP for medical devices, whenever possible (11) 3. Page 6, line 166: not sure if accuracy is the right word here, do you mean recovery? As we fell, the reviewers suggestion gives more precision, we now write e.g. an accuracy (recovery) of 100–109 % for both analytes. 4. Results, page 8: lots of data points for DEHP and MEHP are shown, but several questions remain: was there a correlation between days on ECMO and the levels determined. Was there a correlation between number of red cell transfusions and exposure. In figure 2 and 3: probably there are patients with more than two cannulas and more than one membrane; worthwhile to give this information. Are these patients also having more transfusions and other Medical treatment with PVC components? We agree with the reviewer and changed the manuscript in multiple aspects: Line 221 – 223: The decrease of MEHP after seven days of ECMO in one patient may be due to a limited metabolism but is not verified. The association between duration of ECMO therapy and DEHP or MEHP was tested using Spearman’s correlation coefficient. However, the correlation did not reach statistical significance (r = 0.16, P = 0.53). Line 279 -290: In the present study high values of DEHP and its metabolites are found to be correlated with longer and more intense ECMO (several cannulas, membranes), but not in all patients. We observed a trend of increased DEHP levels after initiation of ECMO therapy. Furthermore, we observed that DEHP and its metabolites were increased when a more intense ECMO treatment (as measured by number of cannulas or number of membranes) was applied. However, there was no positive correlation between duration of ECMO therapy and DEHP levels. This might be due to a rapid increase of DEHP after initiation of the therapy and a steady state during the rest of the treatment. Other factors like the individual metabolism might also have a strong impact on the DEHP-levels. More studies with a larger sample sizes and a more frequent measurement of DEHP-levels are needed in order to further analyse this question. Line 240 – 242: Correlation between DEHP and applied packed cells showed significance (spearman`s correlation coefficient r = 0.59, p<0.01). And finally line 326 – 332: We observed a statistically significant correlation between DEHP-levels and number of packed cells given. This could be due to the critical condition of patients who received a high number of packed cells. Those critical patients might also have received a more intense ECMO therapy. On the other hand, we did not measure the DEHP-levels in the blood products. Former studies indicated a high contamination of the blood products with DEHP, which may have contributed to the DEHP-blood levels in those patients (5, 36). 5. In table 2 it would be of value to have also the DEHP and MEHP values in the blood added. We agree and add these values. 6. Discussion, page 10, line 269: maybe better to formulate differently, high values are found to be correlated with longer and more intense ECMO (several canulas, membranes), but not in all patients. We changed this according to the reviewers suggestion (line 279 ff). 7. Discussion, page 11 line 294 ctd. and page 12 line 317 ctd. seems to be in contrast. Line 294 is 'could be' and in line 317 it is a hypothesis. In my opinion the main reason for higher DEHP in patients without urine output is inhibited elimination, and perhaps more intense treatment plays an additional role, according to the hypothesis. We thank the reviewer for this suggestion and we change the manuscript accordingly. 8. Discussion, page 11, line 300: please add that cell saver treatment includes a washing step. Done. 9. Discussion, page 11, line 314 ctc: according to the individual points in the graphs, it looks like low DEHP is also low MEHP, can you add a remark on this point to the discussion in the part where you discuss MEHP proportion. We agree with the reviewer and add in line 353 ff.: „DEHP and MEHP showed similar dependence, but the MEHP to DEHP ratio was not constant.“ 10. Introduction: although it is true that DEHP is (re)classified as carcinogenic, it has to be clear that the values needed for this effect are far above those for the endocrine disruptive effects. The reviewer is right in saying much higher levels are needed for carcinogenic effects, we thus state in line 77: „Additionally, DEHP in much higher values is classified as a carcinogen for which a non-genotoxic mode of action is predominant.“ Attachments Attachment Submitted filename: DEHP Revision point-by-point reply 16-10-19.doc https://doi.org/10.1371/journal.pone.0224931.r002
25 Oct 2019 Decision Letter - Jaymie Meliker, Editor Exposure of patients to di(2-ethylhexy)phthalate (DEHP) and its metabolite MEHP during extracorporeal membrane oxygenation (ECMO) therapy PONE-D-19-22817R1 Dear Dr. Lepper, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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 enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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. With kind regards, Jaymie Meliker, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0224931.r003
Formally Accepted
23 Jan 2020 Acceptance Letter - Jaymie Meliker, Editor PONE-D-19-22817R1 Exposure of patients to di(2-ethylhexy)phthalate (DEHP) and its metabolite MEHP during extracorporeal membrane oxygenation (ECMO) therapy Dear Dr. Lepper: I am 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 notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, 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. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Jaymie Meliker Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0224931.r004

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