COVID-19 is a respiratory infectious disease caused by SARS-CoV-2, and cardiovascular damage is commonly observed in affected patients. We sought to investigate the effect of SARS-CoV-2 infection on cardiac injury and hypertension during the current coronavirus pandemic.The clinical data of 366 hospitalized COVID-19-confirmed patients were analyzed. The clinical signs and laboratory findings were extracted from electronic medical records. Two independent, experienced clinicians reviewed and analyzed the data.Cardiac injury was found in 11.19% (30/268) of enrolled patients. 93.33% (28/30) of cardiac injury cases were in the severe group. The laboratory findings indicated that white blood cells, neutrophils, procalcitonin, C-reactive protein, lactate, and lactic dehydrogenase were positively associated with cardiac injury marker. Compared with healthy controls, the 190 patients without prior hypertension have higher AngⅡ level, of which 16 (8.42%) patients had a rise in blood pressure to the diagnostic criteria of hypertension during hospitalization, with a significantly increased level of the cTnI, procalcitonin, angiotensin-II (AngⅡ) than those normal blood pressure ones. Multivariate analysis indicated that elevated age, cTnI, the history of hypertension, and diabetes were independent predictors for illness severity. The predictive model, based on the four parameters and gender, has a good ability to identify the clinical severity of COVID-19 in hospitalized patients .Hypertension, sometimes accompanied by elevated cTnI, may occur in COVID-19 patients and become a sequela. Enhancing Ang II signaling, driven by SARS-CoV-2 infection, might play an important role in the renin-angiotensin system, and consequently lead to the development of hypertension in COVID-19. In December 2019, an acute respiratory infectious disease known as "coronavirus disease 2019 (COVID-19)" caused by a novel coronavirus occurred in Wuhan, China , and wasThere were 366 COVID-19-confirmed patients enrolled in this study, who were hospitalized in the Department of Infectious Diseases, Renmin Hospital of Wuhan University, from February 1 to May 1, 2020. Clinical severity was defined for all enrolled COVID-19 patients according to the guidelines of the National Health Commission of China, including four types as mild, moderate, severe, and critical types . We diviThe clinical signs and laboratory findings were extracted from electronic medical records . Two independent, experienced clinicians reviewed and abstracted the data. The recorded information includes demographic data, potential comorbidities, symptoms, signs, laboratory test results. The serum level of hypersensitive troponin I (cTnI) exceeding >40 pg/mL was considered cardiac injury . Blood pFig 1. Serum level of cardiac troponin I (cTnI) was tested in 276 of the 366 patients during hospitalization, among which 8 patients had a history of chronic heart disease  and were therefore excluded. Thus, 268 patients were enrolled to evaluate the effect of SARS-CoV-2 on cardiac injury. Of the 366 patients, 278 had complete blood pressure data. Among these, 88 patients had a history of hypertension before hospitalization and were excluded; therefore, 190 patients were grouped to evaluate the effect of SARS-CoV-2 on blood pressure. Among all 366 subjects, 194 subjects had data available on serum level of cTnI and complete blood pressure data. After the exclusion of the case with a history of chronic heart disease, 186 cases were included to evaluate the association between cTnI, blood pressure, and clinical severity of COVID-19.The screening process for evaluating the effect of SARS-CoV-2 on the cardiovascular system is shown in t-test or the Mann-Whitney test was used to compare the mean of continuous variables, Fisher’s exact test was used with limited data, the χ2 test was used to compare the proportion of categorical variables. Spearman correlation analysis was used to analyze the correlation between variables. The logistic regression model was used to determine factors associated with the clinical severity of COVID-19, and the analysis of receiver operating characteristic (ROC) curves was constructed according to standard procedures. The Youden index, defined as (sensitivity + specificity)– 1, was used to derive a reasonable cut-off value. Calibration of the risk prediction model, comparing the observed and predicted probability, was performed via a visual calibration plot in the R program. A P-value of < 0.05 was considered statistically significant. Statistical analysis was carried out using SPSS software version 21.0 and R version 3.0.Student’s p < 0.001). Males were dominant in the cardiac injury group (86.67%). The cardiac injury was found in 11.19% (30/268) of patients, but 93.33% (28/30) of them were in the severe group. The proportion of cardiac injury was significantly lower in the non-severe group . Moreover, 66.67% (20/30) of cardiac injury patients in the severe group eventually died. The most frequent symptom of patients was fever, followed by cough, fatigue, dyspnea, and chest stuffiness. The incidences of cough, dyspnea, and chest stuffiness were significantly different between the patients with or without cardiac injury . Hypertension was the most frequent comorbidity, while the incidence of diabetes was significantly different between the two groups . The laboratory findings indicated that the patients who suffered from cardiac injury had a higher level of white blood cells, neutrophils, monocytes, procalcitonin, C-reactive protein, lactate, and lactic dehydrogenase compared with the patients without cardiac injury . Correlation analysis showed that white blood cells, neutrophils procalcitonin, C-reactive protein, lactate and lactic dehydrogenase were significantly associated with cTnI, the r values were 0.515 , 0.486 , 0.477 , 0.459 , 0.424  and 0.438 , respectively (Table 2).The results showed that the median age of patients with or without cardiac injury was 74 y/o and 49 y/o with statistical significance . Elevated systolic blood pressure was observed in most of the patients, while diastolic blood pressure was in the normal range. The median values of blood pressure and plasma cTnI levels changes of the 16 patients are shown in Fig 2A. Systolic blood pressure and cTnI levels had a similar trend with the treatment time. In addition, the blood pressure, cTnI, and white blood cells were continuously monitored in one index case . With effective treatment, the patient’s condition improved with regards to symptoms and as evident on chest CT. Meanwhile, the systolic blood pressure and white blood cells reverted to the normal range, and the concentrations of cTnI were also gradually decreased. Among the 190 patients without prior hypertension, the serum levels of components in the renin-angiotensin system, including adrenocorticotrophic hormone, renin, angiotensin Ⅱ (Ang Ⅱ), and aldosterone, were detected in 28 patients. Comparison with healthy controls showed that AngⅡ were significantly elevated in both the normal and elevated blood pressure groups . When comparing the RAS between the normal and elevated blood pressure groups, Ang Ⅱ levels were significantly higher in the latter group .Of the 190 qualified patients, 16 (8.42%) patients had a rise in blood pressure during hospitalization, among which 6 patients were male, and 10 patients were female. As shown in Table 7. Patients in the severe group were significantly older, with a greater proportion of males . In addition, the cTnI, white blood cells, neutrophils, procalcitonin, C-reactive protein, and lactic dehydrogenase of the severe group were significantly higher than those of the non-severe group . In contrast, patients in the severe group had a significantly lower level of lymphocytes median [interquartile range]: 0.78 [0.48–1.29] vs. 1.27 [0.96–1.73], ×109 cells/mL, p < 0.001). Further univariate analysis revealed that the age, sex, cTnI, white blood cells, neutrophils, lymphocytes, C-reactive protein, lactic dehydrogenase, and history of hypertension and diabetes were significantly associated with the clinical severity of COVID-19. In the multivariate analysis, the age, cTnI and history of hypertension and diabetes remained significant independent predictors . The receiver operating characteristic curve of the four independent predictors and gender for clinical severity of COVID-19 is shown in Fig 3A . The calibration indicated that the model was well-calibrated .Results of demographic and laboratory findings between the severe and non-severe group, based on guidelines of the National Health Commission of China, are shown in SARS-CoV-2 has been identified as a single-stranded enveloped 39 RNA virus belonging to the beta-coronavirus genus of the coronaviridae family . ACE2 isSerum cardiac troponin assays have been proposed as the recommended marker of cardiac injury in COVID-19 patients . Huang ath percentile upper reference limit in only 8–12% of positive patients), they are significantly increased in patients with severe disease Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. 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: NoReviewer #2: PartlyReviewer #3: Partly**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't KnowReviewer #2: YesReviewer #3: Yes**********3. Have the authors made all data underlying the findings in their manuscript fully available?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.The Reviewer #1: YesReviewer #2: YesReviewer #3: 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: YesReviewer #2: NoReviewer #3: Yes**********5. Review Comments to the AuthorPlease 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. Reviewer #1: The article is written in a clear manner, however it is unclear at what points the authors use parametric statistics and when they use non-parametric statistics- in this regard they offer no justification for their respective uses. There are only a few minor grammatical errors and only one instance where there is a reference to a paper but no reference number or citation was supplied in the main test. Most importantly, the authors suggest that cardiac injury results from secondary bacterial injury, which based on the design of the trial and that no supporting evidence is provided to this effect , this represents a jump in logic that I do not believe is justifiable. The authors appear to make this supposition based on elevated procalcitonin levels alone- there are published studies that have shown a small subset of patients with severe to critical illness will actually have elevated procalcitonin levels without secondary bacterial co-infection. The confounding effect notwithstanding, this represents a conclusion which is not substantiated by the trial presented here. Moreover, given the confounding effect of hydroxychloroquine, which was the practice at the time of the study, the authors should make note of whether or not HCQ was used in any of these patients, which may actually provide an additional, interesting variable for their analysis. In the section for processes of patient screening, an appendix would be helpful to list what "chronic heart diseases" they considered for exclusion. In the results section, the wording is at times confusing, though technically correct- further revision of this section may help in further iterations of the submission, but do not in themselves constitute grounds for rejection. The very last sentence of the discussion section is too strong of an assertion, perhaps a softer wording of the assertion would be better received. Lastly, the study limitations section does a poor job of discussing the study limitations- heavy revision is advised here- in fact, this section does not discuss any limitations at all and appears to be only a continuation of either the discussion section or the introduction of the conclusions section.Reviewer #2: The study was well planned, conducted, analyzed, and presented. The title is captivating and engaging. The introduction is appropriate and discussion is well written and thorough. The subject matter and idea is novel and well thought-out. The clinical point is very interesting and relevant and the paper should be published pending revisions.The English and syntax of the paper needs a lot of work. The conclusion that bacterial superinfection may be a cause of the cardiac damage needs further evidence from the literature. Please, see attached file.Reviewer #3: This manuscript seeks to address hypertension as a sequalae of COVID-19 disease. Though the clinical association is important, especially as we see more long haul COVID (PASC) in the world population, the manuscript attempts to relate multiple causation for hypertension, including secondary bacterial infection and mycocardial injury during concurrent SARS-CoV-2 infection. The role of ACE2 and the RAS symptom and their relationship to SARS-CoV-2 infectivity and also their role in hypertension would be a more relevant topic to discuss in this manuscript.Major issues for this manuscript include disorganized data that appears to suggest causation of multiple factors, independently, related to COVID-19 disease severity. It is suggested that the manuscript focus on direct hypertension risk factors associated with the SARS-CoV-2 infection and not broad measurements of cTnl and procalcitonin levels we may be unrelated to the development of chronic hypertension.Minor issues of this manuscript include various typographical and grammatical errors. There is also need to expand definitions of mild and moderate severity of disease as well. Please include the National Health Commission of China clinical severity scale and criteria to clarify this in the results section.**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool, AttachmentPONE-D-21-02635_reviewer.pdfSubmitted filename: Click here for additional data file. 10 Apr 2021Response to Reviewers Hypertension as a sequela in patients of SARS-CoV-2 infection (PONE-D-21-02635)We are grateful to reviewers and editors for the comments and have made every effort to modify the manuscript accordingly or to address the concerns. Table 1-7 are replaced with the modified ones. Please see our specific responses below.Journal Requirements:When submitting your revision, we need you to address these additional requirements.https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdfAnswer: Thanks for this suggestion sincerely. The manuscript has been revised according to the PLOS ONE's style requirements.http://learn.aje.com/plos/) for a 15% discount off AJE services. To take advantage of our partnership with Editage, visit the Editage website (www.editage.com) and enter referral code PLOSEDIT for a 15% discount off Editage services. If the PLOS editorial team finds any language issues in text that either AJE or Editage has edited, the service provider will re-edit the text for free.2. We suggest you thoroughly copyedit your manuscript for language usage, spelling, and grammar. If you do not know anyone who can help you do this, you may wish to consider employing a professional scientific editing service. Whilst you may use any professional scientific editing service of your choice, PLOS has partnered with both American Journal Experts (AJE) and Editage to provide discounted services to PLOS authors. Both organizations have experience helping authors meet PLOS guidelines and can provide language editing, translation, manuscript formatting, and figure formatting to ensure your manuscript meets our submission guidelines. To take advantage of our partnership with AJE, visit the AJE website • A clean copy of the edited manuscript (uploaded as the new *manuscript* file)Answer: We are grateful for the visionary suggestion. We have toned down this manuscript.3. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained . If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information.Answer: We greatly appreciate your constructive comment. We have included the ethics statement information in Line 115 - 116 Page 4 as “All participants provided written informed consent and agreed to use their medical record for research purpose.”manuscript:"The current work was supported by the National Natural Science FoundationProject of China (Grant No. 81670304 – D.H.)."We note that you have provided funding information that is not currently declared in your Funding Statement. 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We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see In your revised cover letter, please address the following prompts:a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail  and who has imposed them . Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see We will update your Data Availability statement on your behalf to reflect the information you provide.whdxrmyy@126.com) for researchers who meet the criteria for access to confidential data.”Answer: We re-make the Data Availability statement as suggested in Line 458 - 462 Page 15 as “Data cannot be shared publicly because of the contents including information that could compromise research participant privacy/consent. Data are available from the Renmin Hospital of Wuhan University Ethics Committee , this represents a jump in logic that I do not believe is justifiable. The authors appear to make this supposition based on elevated procalcitonin levels alone- there are published studies that have shown a small subset of patients with severe to critical illness will actually have elevated procalcitonin levels without secondary bacterial co-infection. The confounding effect notwithstanding, this represents a conclusion which is not substantiated by the trial presented here. Answer: Thank you a lot for your important comment again. We agree with the reviewer and have revised the manuscript accordingly as follows.First, we agree that it is not rigorous enough to draw the conclusion that cardiac injury results from secondary bacterial injury and decide to remove it. we have adjusted the discussion about cardiac injury in Line 245 - 252 Page 11 as “In this study, older patients with diabetes are more likely to suffer from cardiac injury. Our further analysis shows that the level of white blood cells, neutrophils, procalcitonin, C-reactive protein, lactate, and lactic dehydrogenase were positively associated with cardiac injury. Besides, cardiac injury occurred mostly in severe patients. Consequently, we hypothesize that severe type of COVID-19 characterized by acute inflammation response might be more prone to cardiac injury, especially in patients with preexisting cardiovascular disease. ” Besides, according to your suggestion, we have rearranged our data of renin-angiotensin system (RAS). These results, integrated into Table. 5A&B, suggesting that Ang Ⅱ levels were significantly higher in the elevated blood pressure group. Thus, we discuss in Line 300-308 Page13 as “On the other hand, sixteen patients with elevated blood pressure show significantly higher levels of cTnI than those normal blood pressure patients. Several studies have demonstrated Ang II direct or indirect effects on cardiomyocytes, some of which were related to pro-inflammatory and pro-hypertrophic responses. Especially when the balance between the ACE and ACE2 was disrupted in COVID-19 patients, the increase in Ang II actions could lead to myocardial inflammation, oxidative stress, and myocyte apoptosis. This hypothesis explains why elevated blood pressure could occur in parallel with mild cardiac injury of COVID-19 patients. ” Finally, we resummarize our conclusions in the Abstract part (Line 57 - 60 Page 2) as “Hypertension, sometimes accompanied by elevated cTnI, may occur in COVID-19 patients and become a sequela. Enhancing Ang II signaling, driven by SARS-CoV-2 infection, might play an important role in renin-angiotensin system and consequently lead to the development of hypertension in COVID-19”4.Moreover, given the confounding effect of hydroxychloroquine, which was the practice at the time of the study, the authors should make note of whether or not HCQ was used in any of these patients, which may actually provide an additional, interesting variable for their analysis. Thanks for this suggestion sincerely. We have checked carefully and rearranged each patients’ clinical and self-reported data in this study, and all subjects had no medical history of hydroxychloroquine.5.In the section for processes of patient screening, an appendix would be helpful to list what "chronic heart diseases" they considered for exclusion. In the results section, the wording is at times confusing, though technically correct- further revision of this section may help in further iterations of the submission, but do not in themselves constitute grounds for rejection. Answer: We are grateful for the visionary suggestion. We have redefined "chronic heart diseases" in the Method part (Line 119 - 120 Page 5) and Figure legends part (Line 452-453 Page 21), as “Chronic heart disease includes ischemic heart disease, arrhythmia, valvular disease, and heart failure.”6.The very last sentence of the discussion section is too strong of an assertion, perhaps a softer wording of the assertion would be better received. Lastly, the study limitations section does a poor job of discussing the study limitations- heavy revision is advised here- in fact, this section does not discuss any limitations at all and appears to be only a continuation of either the discussion section or the introduction of the conclusions section.Answer: Thanks for this suggestion sincerely. We have adjusted the last sentence of the discussion section in Line 300 - 308 Page13, as “On the other hand, sixteen patients with elevated blood pressure show significantly higher levels of cTnI than those normal blood pressure patients. Several studies have demonstrated Ang II direct or indirect effects on cardiomyocytes, some of which were related to pro-inflammatory and pro-hypertrophic responses. Especially when the balance between the ACE and ACE2 was disrupted in COVID-19 patients, the increase in Ang II actions could lead to myocardial inflammation, oxidative stress, and myocyte apoptosis. This hypothesis explains why elevated blood pressure could occur in parallel with mild cardiac injury of COVID-19 patients. We have re-written the part of study limitations in Line 309 - 320 Page 14 as “In the present study, we propose that hypertension is probably a sequela of SARS-CoV-2 infection. Although several studies of COVID-19 have been reported, there are few reports about the sequela of the disease likely due to lack of long-term clinical follow-up, which also applies to our present research. Next, it is difficult to analyze whether the blood pressure of COVID-19 patients with preexisting hypertension is further increased. Consequently, many patients could not be incorporated in the analysis because of history of hypertension, which results in a relatively low sample size. Besides, the present study uncovered rising Ang II as one possible mechanism that might result in hypertension in COVID-19. However, due to a lack of detection about ACE2 levels and other components, therefore, we cannot gain a comprehensive view of the virus-induced imbalance of RAS pathway. ” Reviewer #2: The study was well planned, conducted, analyzed, and presented. The title is captivating and engaging. The introduction is appropriate and discussion is well written and thorough. The subject matter and idea is novel and well thought-out. The clinical point is very interesting and relevant and the paper should be published pending revisions.The English and syntax of the paper needs a lot of work. The conclusion that bacterial superinfection may be a cause of the cardiac damage needs further evidence from the literature. Please, see attached file.Answer: We are grateful for the visionary suggestion. We agree with the reviewer and have revised the manuscript accordingly as follows.First, we agree that it is not rigorous enough to draw the conclusion that cardiac injury results from secondary bacterial injury and decide to remove it. we have adjusted the discussion about cardiac injury in Line 245 - 252 Page11 as “In this study, older patients with diabetes are more likely to suffer from cardiac injury. Our further analysis shows that the level of white blood cells, neutrophils, procalcitonin, C-reactive protein, lactate, and lactic dehydrogenase were positively associated with cardiac injury. Besides, cardiac injury occurred mostly in severe patients. Consequently, we hypothesize that severe type of COVID-19 characterized by acute inflammation response might be more prone to cardiac injury, especially in patients with preexisting cardiovascular disease. ” Besides, according to your suggestion, we have rearranged our data of renin-angiotensin system (RAS). These results, integrated into Table. 5A&B, suggesting that Ang Ⅱ levels were significantly higher in the elevated blood pressure group. Thus, we discuss in Line 300 - 308 Page13 as “On the other hand, sixteen patients with elevated blood pressure show significantly higher levels of cTnI than those normal blood pressure patients. Several studies have demonstrated Ang II direct or indirect effects on cardiomyocytes, some of which were related to pro-inflammatory and pro-hypertrophic responses. Especially when the balance between the ACE and ACE2 was disrupted in COVID-19 patients, the increase in Ang II actions could lead to myocardial inflammation, oxidative stress, and myocyte apoptosis. This hypothesis explains why elevated blood pressure could occur in parallel with mild cardiac injury of COVID-19 patients. ” Finally, we resummarize our conclusions in the Abstract part (Line 57 - 60 Page 2) as “Hypertension, sometimes accompanied by elevated cTnI, may occur in COVID-19 patients and become a sequela. Enhancing Ang II signaling, driven by SARS-CoV-2 infection, might play an important role in renin-angiotensin system and consequently lead to the development of hypertension in COVID-19” Reviewer #3: This manuscript seeks to address hypertension as a sequalae of COVID-19 disease. Though the clinical association is important, especially as we see more long haul COVID (PASC) in the world population, the manuscript attempts to relate multiple causation for hypertension, including secondary bacterial infection and mycocardial injury during concurrent SARS-CoV-2 infection. The role of ACE2 and the RAS symptom and their relationship to SARS-CoV-2 infectivity and also their role in hypertension would be a more relevant topic to discuss in this manuscript.Major issues for this manuscript include disorganized data that appears to suggest causation of multiple factors, independently, related to COVID-19 disease severity. It is suggested that the manuscript focus on direct hypertension risk factors associated with the SARS-CoV-2 infection and not broad measurements of cTnl and procalcitonin levels may be unrelated to the development of chronic hypertension.Answer: We greatly appreciate your constructive comment. According to your suggestion, we have rearranged our data of renin-angiotensin system (RAS). These results, integrated into Table. 5A&B, suggesting that the increase in Ang II actions may direct or indirect effects on cardiomyocytes. Thus, we discuss in Line 300 - 308 Page13 as “On the other hand, sixteen patients with elevated blood pressure show significantly higher levels of cTnI than those normal blood pressure patients. Several studies have demonstrated Ang II direct or indirect effects on cardiomyocytes, some of which were related to pro-inflammatory and pro-hypertrophic responses. Especially when the balance between the ACE and ACE2 was disrupted in COVID-19 patients, the increase in Ang II actions could lead to myocardial inflammation, oxidative stress, and myocyte apoptosis. This hypothesis explains why elevated blood pressure could occur in parallel with mild cardiac injury of COVID-19 patients. ” Besides, we resummarize our conclusions in the Abstract part (Line 57 - 60 Page 2) as “Hypertension, sometimes accompanied by elevated cTnI, may occur in COVID-19 patients and become a sequela. Enhancing Ang II signaling, driven by SARS-CoV-2 infection, might play an important role in renin-angiotensin system and consequently lead to the development of hypertension in COVID-19”Minor issues of this manuscript include various typographical and grammatical errors. There is also need to expand definitions of mild and moderate severity of disease as well. Please include the National Health Commission of China clinical severity scale and criteria to clarify this in the results section.Answer: Thank you for your correction. According to your suggestion, we have defined mild and moderate severity of disease in the Method part (Line 90 - 93 Page 4) as “Mild type is defined as mild clinical symptoms and no pneumonia manifestation found in imaging. Moderate cases refer to those who present with fever and respiratory tract symptoms, etc. And have pneumonia manifestations found in imaging.”Besides, in the Result part (Line 207 Page 9), the division criteria have been supplemented, as “Results of demographic and laboratory findings between the severe and non-severe group, based on guidelines of the National Health Commission of China, are shown in Table 6.”AttachmentResponse to reviewers - ver1.docxSubmitted filename: Click here for additional data file. 15 Apr 2021Hypertension as a sequela in patients of SARS-CoV-2 infectionPONE-D-21-02635R1Dear Dr. Hu,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.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.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at onepress@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 Kind regards,Bhagwan Dass, MDAcademic EditorPLOS ONEAdditional Editor Comments :Reviewers' comments: 19 Apr 2021PONE-D-21-02635R1 Hypertension as a sequela in patients of SARS-CoV-2 infection Dear Dr. Hu: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. onepress@plos.org.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 plosone@plos.org. If we can help with anything else, please email us at Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staffon behalf ofDr. Bhagwan Dass Academic EditorPLOS ONE


Our study aimed to test the hypothesis that tc-artPCO2 can detect inadequate tissue perfusion during hemorrhagic shock and resuscitation.Despite much evidence supporting the monitoring of the divergence of transcutaneous partial pressure of carbon dioxide (tcPCO2. A pulmonary artery catheter (PAC) and pulse index continuous cardiac output (PiCCO) were used to monitor cardiac output (CO) and several hemodynamic parameters. The relationships of tc-artPCO2 with the study parameters and systemic oxygen delivery (DO2) were analyzed.This prospective animal study was performed using female pigs at a university-based experimental laboratory. Progressive massive hemorrhagic shock was induced in mechanically ventilated pigs by stepwise blood withdrawal. All animals were then resuscitated by transfusing the stored blood in stages. A transcutaneous monitor was attached to their ears to measure tcPCO2 level markedly increased as CO decreased. There were significant correlations of tc-artPCO2 with DO2 and COs . The critical level of oxygen delivery (DO2crit) was 11.72 mL/kg/min according to transcutaneous partial pressure of oxygen (threshold of 30 mmHg). Receiver operating characteristic curve analyses revealed that the value of tc-artPCO2 for discrimination of DO2crit was highest with an area under the curve (AUC) of 0.94, followed by shock index , and lactate .Hemorrhage and blood transfusion precisely impacted hemodynamic and laboratory data as expected. The tc-artPCO2 monitoring can sensitively detect inadequate systemic oxygen supply during hemorrhagic shock. Further evaluations are required in different forms of shock in other large animal models and in humans to assess its usefulness, safety, and ability to predict outcomes in critical illnesses.Our observations suggest the less-invasive tc-artPCO Hemorrhagic shock is a life-threatening condition, with a significant loss of intravascular volume, decreased cardiac output (CO), decreased tissue perfusion pressure, and cellular hypoxia, resulting in multiple organ damage and death , 2. The The pulmonary artery catheter (PAC) provides continuous monitoring of comprehensive hemodynamic parameters, including stroke volume, CO, mixed venous oxygen saturation, and intracardiac pressure, with several additional calculated variables to guide diagnosis and treatment . The pul2) and carbon dioxide (tcPCO2), which can non-invasively assess arterial partial pressure of oxygen (artPO2) and carbon dioxide (artPCO2), respectively, has been investigated for several decades  parameters obtained by PiCCO technology  included the mean arterial pressure (MAP), SV (SVTPTD), CO (COTPTD), global end-diastolic blood volume (GEDV), stroke volume variation (SVV), pulse pressure variation (PPV), cardiac function index , cardiac power output . The shock index (SI), defined as heart rate divided by systolic blood pressure, at each measurement point was calculated. SI of > 1.0 was indicative of worsening hemodynamic status and shock [Hemodynamic parameters measured by PAC (pulmonary artery thermodilution [PATD]) included the central venous pressure (CVP), pulmonary artery wedge pressure (PAWP), stroke volume , which was derived from pulse oximetry readings , was monitored simultaneously. The Masimo Radical-7 uses transcutaneous, multi-wavelength analysis for non-invasive measurement of arterial oxygen saturation, PI, and pleth variability index (PVI), which are measures of local blood flow. A sensor  was attached to the tail after clipping the hair. Esophageal temperature and heart rate were also recorded .2, artPCO2, hemoglobin (Hb), and lactate, using a blood gas analyzer .Arterial blood samples were withdrawn anaerobically from the PiCCO catheter and collected in a plastic syringe heparinized with 1000 U/mL of sodium heparin , using an evacuation technique to minimize sample dilution. The blood samples were analyzed by an investigator blinded to the experiments immediately after collection (< 5 min) to measure artPO2) capacity fails to satisfy the metabolic oxygen need in the tissue. It is well established that tissues exhibit a level of systemic DO2, known as the critical DO2 (DO2 crit), below which the extraction cannot increase sufficiently to sustain O2 uptake; O2 consumption then becomes supply-dependent [2 was calculated using the following equation: DO2 (mL/kg/min) = CO × hemoglobin [Hb] × 1.36 × arterial oxygen saturation (SaO2) +  [2 was used to define DO2crit since tcPO2 reflects tissue oxygenation under experimental conditions. Given that the lowest baseline tcPO2 associated with survival was 28 mmHg [2 was set as 30 mmHg. This is consistent with previous studies, which demonstrated that tcPO2 values < 25 mmHg reflects a 50% decrease in oxygen consumption, preceding cardiac arrest [2 value of 40 mmHg is a critical artPO2 in the subcutaneous tissue [An inappropriate level of systemic oxygen delivery (DOependent –26. DO2  0.0031) . In thisc arrest , and tha2 and artPCO2. Repeated one-way analysis of variance (ANOVA) followed by Dunnett's correction and Friedman test followed by Dunn's correction were performed for post-hoc comparisons of normally and non-normally distributed data, respectively. Spearman's correlation coefficients (r) were calculated to evaluate the correlation between any two parameters. To examine the accuracy of tc-artPCO2, SI, and arterial lactate for predicting DO2crit, receiver operating characteristic (ROC) curve analyses were performed. The area under the curve (AUC) between two pairs of potential predictors was compared using a nonparametric test. Statistical significance was defined as a two-sided p-value of < 0.05. All statistical analyses were performed using GraphPad Prism version 8.3.0  and Microsoft Excel .Values are expressed as mean ± standard error of the mean. An unpaired two-tailed Student’s t-test or Mann–Whitney U test was performed to compare two independent groups, as appropriate. Linear regression and Bland–Altman analyses were performed to determine the correlation between tcPCOAll six pigs were included, and 42 paired measurements of each of their variables were analyzed. No death occurred during the experiments.2, MAP, heart rate, CVP, SI, PI, and comprehensive hemodynamic parameters obtained by PAC or PiCCO, such as CO and SV , linear regression demonstrated that there was a strong relationship between tcPCO2 and artPCO2 . In Bland–Altman analysis, the mean bias was 4.1 ± 5.4 mmHg. In contrast, using 30 measurement points of the hypovolemic status, there was no relationship between tcPCO2 and artPCO2 , and the mean bias based on Bland–Altman analysis was 16.2 ± 11.4 mmHg , COTPTD (r =  − 0.74), and tcPO2 (r =  − 0.89)   < 2.5, 2.5 ≤ COPATD < 3.0, 3.0 ≤ COPATD < 4.0, and 4.0 ≤ COPATD. There was a negative linear trend between tcPCO2 and CO categories: with the lowest tc-artPCO2 value (2.6 ± 1.0 mmHg) when CO was > 4.0 L/min and the highest (24.6 ± 2.9 mmHg) when CO was < 2.5 L/min. Conversely, there was a positive linear trend between tcPO2 and CO categories  Fig. . Data fo2 at baseline (15.9 ± 2.7 mL/kg/min), significant declines in DO2 at BW10, BW20, BW30, and BT10 were observed . After all the stored blood was transfused (BT30), DO2 returned to baseline value (16.2 ± 1.9 mL/kg/min). There were significant positive correlations of DO2 with tcPO2 and MAP , and significant negative correlations of DO2 with tc-artPCO2, SI, heart rate, and lactate   was calculated as 11.72 mL/kg/min, according to the predetermined tcPO2 threshold of 30 mmHg . The AUCs showed that the predictive values of tc-artPCO2, SI, and lactate were 0.94 , 0.78 (0.63–0.93), and 0.65 (0.47–0.82), respectively, with respect to the prediction of DO2crit for the transition from aerobic to anaerobic metabolism  and specificity (77%) for predicting DO2crit, whereas an SI cut-off of 1.13 was identified as the optimal value   and lactate (P = 0.001)  compared with SI and lactate BW30 .The critical level of DOmHg see “”. ROC cu2 as a rapid yet sensitive indicator of hemorrhagic shock in a mechanically ventilated pig model during progressive hemorrhagic shock and resuscitation. We verified the hypotheses that tcPCO2 can non-invasively estimate and track artPCO2 in euvolemic conditions and that tcPCO2 and artPCO2 decoupled during hemorrhagic shock. To the best of our knowledge, this study showed, for the first time, (1) strong associations of tc-artPCO2 with DO2 and CO, which were appropriately measured based on both PAC and PiCCO, and (2) significantly superior AUC for tc-artCO2, compared with those for SI or arterial lactate, which are independently associated with physiological and clinical outcomes in hemorrhagic shock [2 reflects the variations in CO and DO2 and can be a valid, non-invasive indicator of impaired DO2 during hypovolemic shock.In this study, we assessed the usefulness of tc-artPCOst time,  strong aic shock , 32–34. 2 monitoring is to measure artPCO2 non-invasively and continuously, preventing the need to perform multiple blood gas analyses and guiding therapeutic interventions. In previous studies, tcPCO2 and artPCO2 reportedly decoupled during circulatory failure and are associated with poor outcomes in critically ill patients [2 is less invasive, rapid, and easy to use. Therefore, monitoring tcPCO2 can be used as a common utility, especially in emergency departments and intensive care units. In particular, in patients on respirator, monitoring tcPCO2 can estimate artPCO2 and detect respiratory complications as a common utility, whereas tc-artPCO2 can estimate low CO and/or low DO2 for hemodynamic and metabolic assessments during shock.The primary purpose of tcPCOpatients , 20, 21.2 as a marker of hypoperfusion [2 and anaerobic production of CO2 [2 content in tissues  based on the high diffusivity of CO2 gas. In a pig model with acute lung injury, tcPCO2 is an acceptable surrogate for artPCO2 in hemodynamically stable states; however, tcPCO2 and artPCO2 decoupled during shock [2 measured from the ear lobe at study inclusion was significantly higher in patients with septic shock than in controls. Additionally, there was a significantly greater gradient between tcPCO2 and artPCO2 or end-tidal CO2 (etCO2) in patients with septic shock than in controls [2 is an early indicator of circulatory failure and a prognostic factor of increased morbidity in patients with cardiopulmonary bypass after cardiac surgery [2 is not widely used in clinical practice [Previous studies support elevated tissue PCOerfusion –38. The n of CO2 . Currentng shock . This iscontrols . Increas surgery . Despitepractice  and rema2 and tcPCO2 gradient (NICO2G) could serve as a proxy for the severity of hemorrhage-induced metabolic debt, as indicated by elevated arterial lactate levels [2 ; better for tcPCO2 ; and best for NICO2G . The findings that tcPCO2 increased during hemorrhage and correlated well with peripheral hypoperfusion even as artPCO2 remained constant [2 monitoring may not be suitable for serial hemodynamic assessments in patients with lung injury or under mechanical ventilation, as adjustments of respiratory setting could be frequently required. Additionally, etCO2 can be decreased in shock states because of impaired pulmonary blood flow. Thus, tc-artPCO2 adopted in our study might be more useful for detecting shock states in ventilated patients than NICO2G. Moreover, it was reported that an increase in arterial lactate occurred later than the decreases in CO and DO2 in a pig model with hemorrhagic shock due to a time difference in the occurrence of tissue and circulating lactic acid [2 and/or CO could be more appropriate markers for shock than lactate levels. Our efforts to measure hemodynamic parameters with two different established methods , and using DO2 as a primary outcome, strengthened the results of this study.In a pig model with lethal hemorrhagic shock, Belenkiy et al. demonstrated that the non-invasive etCOe levels . Linear constant  were contic acid . Thus, D2, tcPO2 measurement allows for continuous monitoring of tissue oxygenation, which is compromised during the early phase of hemorrhagic shock and is one of the last measures to be restored during resuscitation [2 responded rapidly to changes in CO during hemorrhage and blood transfusion (Fig. 2 in response to hemorrhage and fluid infusion [2 was more rapidly responsive than tcPCO2 and arterial lactate [2 cannot be overemphasized [2 depends on FIO2, which should be managed frequently during critical care. Thus, tcPO2 monitoring without reference to FIO2 can be misleading [Besides tcPCOcitation . In thision Fig. . Consistinfusion , 46. In  lactate . Howeverphasized  because sleading .Our study has several limitations that should be addressed in future investigations. First, the small sample size could have resulted in a type 1 error. However, to address this limitation, we have made efforts using both PAC and PiCCO systems as hemodynamic monitors for ensuring the quality of experiments. Second, this study included only female animals to minimize heterogeneity. Future studies should include both male and female animals to investigate the role of sex in susceptibility to shock. Lastly, as this study focused only on hemorrhagic shock status, our present findings cannot be extrapolated to other shock etiologies. Thus, further studies are needed to replicate these findings for all types of shocks before extrapolating the data to other critical illnesses.2 monitoring is a minimally invasive technique that could be a rapid yet sensitive indicator of evolving hemorrhagic shock during mechanical ventilation and that tc-artPCO2 is superior to SI and arterial lactate levels. The present study results are encouraging, and the data clearly strengthen previous literature on techniques to monitor tissue O2 and CO2 partial pressures. Further evaluations are required in different forms of shock in other large animal models and in humans to assess its usefulness, safety, and ability to predict outcomes in critical illnesses.Using a precise pig model, we demonstrated that continuous tc-artPCO


Further, clinical studies in adult CKD have observed cardiotoxicity associated with FGF23. Data regarding prevalence and determinants of FGF23 excess in children with CKD are limited. This review summarizes current data and discusses whether FGF23 may be a key driver of LVH in pediatric CKD.Cardiovascular diseases (CVD) are a hallmark in pediatric patients with chronic kidney disease (CKD) contributing to an enhanced risk of all-cause and CV morbidity and mortality in these patients. The bone-derived phosphaturic hormone fibroblast growth factor (FGF) 23 progressively rises with declining kidney function to maintain phosphate homeostasis, with up to 1,000-fold increase in patients with kidney failure requiring dialysis. FGF23 is associated with the development of left ventricular hypertrophy (LVH) and thereby accounts to be a CVD risk factor in CKD. Experimentally, FGF23 directly induces hypertrophic growth of cardiac myocytes  Chronic kidney disease (CKD) is a significant global health issue and defined as gradual loss of kidney function ultimately leading to irreversible kidney damage . CKD pata priori. To make matters worse, different hemodynamic stimuli e.g., hypertension, arterial stiffness, volume expansion, and anemia can occur simultaneously in CKD, resulting in distinct alterations of LV geometry  . There igeometry . Hypertrgeometry , 21. FGFgeometry –24. Vicegeometry . Interesgeometry . Since, Vascular injury is promoting CVD as well. Changes in vascular tissue, leading to atherosclerotic and arteriosclerotic alterations and/or vascular calcification, are very common in CKD. Plaque and atheroma formation during atherosclerosis start with accumulation of macrophages in the vascular intima followed by aggregation of lipids, different fibers of collagen and smooth muscle cells. At the same time, calcification with the development of atherosclerotic lesions at the intima occurs causing stenosis and local closures of the artery. Circulating endothelial progenitor cells (EPCs) contribute to angiogenetic processes where they are recruited to the heart vessels after injury or damage. Studies show a reduced number of EPCs with impaired function in CVD .In arteriosclerosis, the process of arterial stiffening and arterial calcification results in arteries with thicker intima and media, which affects their elasticity. The increased wall thickness together with a lumen enlargement, resulting in higher systolic blood pressure and arterial stiffening, characterize the vascular remodeling processes during arteriosclerosis. The main consequences of arterial stiffening are LVH and an altered coronary perfusion .Over the past decade, vascular calcification in combination with chronic inflammation have come into focus as another risk factor for CVD in CKD, driving disease progression particularly in children on chronic dialysis . In combThe pro-inflammatory marker IL-6 is involved in the development of atherosclerotic lesions by recruiting inflammatory cells. Circulating plasma level of IL-6 were elevated in a cohort of stable haemodialysis patients enrolled in the HEMO study suggesting IL-6 to be a strong predictor of CV and all-cause mortality , 36. FurTNF-α is induced by inflammatory stimuli and stimulates the immune response. It was shown to be upregulated in kidney disease and LVH in patients receiving dialysis . IncreasIn children, LVH develops early in mild and moderate chronic renal insufficiency and exacerbates with kidney failure requiring dialysis , 11, 41.Endothelial dysfunction (ED) measured by impaired endothelium-dependent flow-mediated dilation (FMD) is observed in children with advanced kidney failure, on chronic dialysis and after renal transplantation , 49. Nit2D3  1/α-Klotho complex in the kidney to mediate downregulation of sodium-dependent phosphate co-transporters (NaPi2a and NaPi2c) that results in decreased tubular phosphate reabsorption and finally lower serum phosphate levels . In earl2D3 . Thus, rThus, alterations to levels of FGF23, which progressively increase together with changes in the metabolism of phosphate, calcium, PTH and/or 1,25D in worsening renal dysfunction with CKD result in CKD-MBD. This complex clinical syndrome is characterized by abnormalities in bone and mineral metabolism as well as extra-skeletal calcification resulting in fractures and bone deformities and, most prominently, in poor growth , 70, whiIn early CKD, circulating FGF23 levels rise exponentially and are up-to 1,000-fold enhanced in kidney failure , 66. Ele2 is associated with a higher prevalence of LVH  or calcineurin, but not by the use of MAP kinase, PI3 kinase or Akt inhibitors. Also, the use of PD173074 to block all FGFRs reduced LV mass and the cardiac expression of genes associated with LVH  could be reversed by incubation with cyclosporine A, losartan and spironolactone  followed by inducing CKD using an adenine-containing diet did not prevent hyperparathyroidism. Rather increased phosphate level as well as more pronounced cardiac hypertrophy were observed compared to uremic controls leading the authors to the conclusion that elevated FGF23 level in CKD may have a protective role to maintain cardiac homeostasis . W. W109). Several studies target dietary phosphate restriction to lower FGF23 levels . TherebyFurther studies included the treatment of Vitamin D deficiency in 5/6 nephrectomized rats with calcitriol that reduced the expression of FGF23 and FGFR4 in the heart inactivating calcineurin/NFAT signaling and thereby reduced the development of LVH . HoweverCurrently, FGF23 concentrations are not routinely measured in patients. One reason is the absence of reliable immunoassays for measurement of FGF23, which are validated for clinical use , 122. AnExperimental and clinical data reviewed here suggest it remains reasonable to consider that reducing elevated level of FGF23 is potentially a promising therapeutic pathway for reducing CVD in CKD in adult and children. Randomized clinical trials targeting the pathophysiology of FGF23-induced CVD are needed to help clarify the impact of FGF23 on LVH in CKD.In summary, the scientific community gained a lot of knowledge about the regulation and effects of FGF23. Although FGF23 mainly regulates phosphate homeostasis, in adults as well as in pediatric CKD the levels of FGF23 are markedly increased with progressing kidney failure and high FGF23 levels are strongly associated with left ventricular hypertrophy. However, a direct link to other CKD associated CV abnormalities needs to be proven in pediatric patients. In fact, CV events e.g., cardiac arrest and arrhythmia, are the leading cause of death in children with CKD and a dysregulated FGF23 metabolism may additionally have detrimental effects on the cardiovascular system. Regardless, many findings are contradictory and large prospective clinical studies are needed to elucidate the exact pathological mechanisms of FGF23 induced CVDs in pediatric CKD.AG performed literature research, drafted the manuscript, and designed the figures. MS critically discussed content of review and all revisions of the manuscript. DH critically discussed the content of the review and revised the manuscript. ML-N critically discussed the content of the review and revised the manuscript and the figures. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Acute severe asthma is a life-threatening medical emergency. Characteristics of asthma include increased airway resistance and dynamic pulmonary hyperinflation that can manifest in dangerous levels of hypercapnia and acidosis, with significant mortality and morbidity. Severe respiratory distress can lead to endotracheal intubation followed by mechanical ventilation, which can cause increased air trapping with dynamic hyperinflation, predisposing the lungs to barotraumas.2R ProLUNG® (Estor) with protective low-tidal-volume ventilation, in a Caucasian patient with near-fatal asthma and with no response to conventional therapy.The present case report describes the use of the minimally invasive ECCO2R membrane ProLUNG® (Estor) with ultra-protective low-tidal-volume ventilation can be successfully applied to limit the risk of severe barotrauma during invasive mechanical ventilation. ECCO2R ProLUNG® is a partial respiratory support technique that, based on the use of an extracorporeal circuit with a gas-exchange membrane, achieves relevant CO2 clearance directly from the blood using double-lumen venous-venous vascular access, at blood flow in the range of 0.4–1.0 L/minute.Since hypercarbia rather than hypoxemia is the primary abnormality in status asthmaticus, a rescue therapeutic strategy combining the ECCO Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation . It is dStatus asthmaticus is difficult to define, but we can affirm that any patient not responding to initial doses of nebulized bronchodilators should be considered to have status asthmaticus . Risk fa2 and thus to hypercapnic acidosis. Therefore, a balance is required between the hypoventilation aiming to protect the lung from ventilator-induced lung injury and the gas exchange. For this purpose, a successful strategy may be to combine a decapneization technique with our protective ventilation, which otherwise could not be applied because of hypercapnia.This setting can easily lead to a further increase in CO2 through the ProLUNG® (Estor) with no modifications of ventilator settings. A CO2 removal machine allows for rescue time to treat the lung illness. Decapneization represents an intermediate level between pulmonary ventilation and extracorporeal membrane oxygenation (ECMO). It is a simple veno-venous system with low blood flow that, thanks to the presence of an oxygenator and a blood filter, enables the removal of 20 to 35% of carbon dioxide. Blood is taken, treated, and then reinfused via a single double-lumen catheter inserted into the femoral or jugular vein. A membrane oxygenator for CO2 removal is used alone or in combination with continuous renal replacement therapy (RRT). In our case, CO2 removal was used alone. It is not a method for oxygenation, so we cannot use it as “lung replacement” therapy, but rather as “lung support” or “protective” therapy.In this way, we can remove the excess CO2) of 53 mm Hg, and partial pressure of carbon dioxide (PaCO2) of 50 mm Hg. She failed to respond to nebulized salbutamol and ipratropium and to intravenous salbutamol and magnesium, and therefore was transferred to the intensive care unit (ICU), where noninvasive ventilation (NIV) was started. Despite this strategy, she exhibited pronounced use of accessory respiratory muscles and rapidly required orotracheal intubation (OTI). The ventilator was set according to guidelines of mechanical ventilation for severe acute asthma, based on low tidal volume 5–6 mL/kg of ideal body weight (IBW), respiratory rate of 10–12 breaths/minute, and prolonged expiratory time. Sedation and neuromuscular-blocking agents were needed to ensure this degree of hypoventilation. The dynamic hyperinflation was assessed by measuring the plateau pressure (after a transient inspiratory pause), which was about 30 mmHg with low blood pressure. We performed a 60-second apnea test, which confirmed the correlation between the lung hyperinflation and the hemodynamic sufferance. Therefore, the ventilatory patterns were modified by reducing tidal volume to 4 mL/kg and respiratory rate to 10 breaths/min (timeline T0) , pH of 7.01, and PaO2 of 60 mmHg. A first chest computed tomography (CT) scan was performed  (timeline T1) , 30 mcg/minute of salbutamol by continuous infusion, and 40 mg/day of intravenously administered methylprednisolone. No adjustments were made to the setting of the mechanical ventilation in order to keep the lung-protective strategy by maintaining very low tidal volumes (about 4 mL/kg) and decreased respiratory rate (RR about 10 breaths/minute). Sedation and neuromuscular-blocking agents continued to be applied. No hypotension or other hemodynamic complications occurred during the CO2 removal. Several arterial blood gases were taken to monitor the gas exchange, and a gradual improvement of hypercapnia was observed. After 48 hours of decapneization, the patient’s clinical status was significantly improved, with decreased wheezing and return to normal pH value, with a marked reduction in PaCo2 (55 mmHg) (timeline T2)  Fig. . A seconA substantial percentage (4%) of cases of acute asthma exacerbation require admission to the ICU, and one third of these patients require endotracheal intubation and mechanical ventilation , 6.Risk factors for near-fatal asthma (NFA) requiring invasive mechanical ventilation include a younger age at presentation, poor compliance with drug therapy, poor outpatient follow-up, more than three emergency department visits in the preceding year, recent hospital admission, a prior episode of NFA, and prior mechanical ventilation . In the 2R) seems particularly interesting in the case of asthmatic patients where early protective mechanical ventilation  fails. The ECCO2R membrane allows the use of ultra-protective mechanical ventilation with a drastic reduction in tidal volume (3–4 mL/kg IBW) and minute ventilation, immediately limiting lung overinflation and gas trapping, and reducing the barotrauma.In conclusion, this rescue technique (ECCO


High-normal blood pressure has been suggested to associate with target organ damage and higher left ventricular mass index (LVMI). Our aim is to find the association between people with high-normal blood pressure and their left ventricular mass index.  Given a total of 181 people with office blood pressure, 24-hour ambulatory blood pressure monitoring, 35 of them are normotensive (BP < 130/85 mm Hg), and 146 people with high-normal blood pressure (BP 130–139/85–89 mm Hg), divide the high-normal blood pressure group into dipper and nondipper according to their ABPM in 24 hours. All of them were performed with echocardiography to calculate LVMI. p < 0.05) than in the dipper group (116 + 11) mmHg, indicating the mean systolic BP is associated with the dipper type (p < 0.05); furthermore, the higher nocturnal blood pressure is associated with the nondipper group significantly (p < 0.05), and LVMI ((121 ± 11) g/m2) of the nondipper group is also significantly higher than in the dipper group's LVMI ((108 ± 12) g/m2) (p < 0.05). The multivariate linear regression analyses revealed significant and independent associations of LVMI with these factors: triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL-C), and coefficient of variation of systolic and diastolic blood pressure in 24 hours.  After adjusting for potential confounding factors, mean systolic blood pressure (BP) of the nondipper group is (119 + 9) mmHg in 24 h, which is significantly higher ( After multiple relevant clinical confounding factors were adjusted, patients with dipper and nondipper high-normal blood pressure had higher LVMI. Abnormalities in circadian blood pressure variability may be associated with the left ventricular hypertrophy. According to the 2020 international hypertension guideline, high-normal blood pressure was defined as systolic BP between 130 and 139 mmHg and/or diastolic BP between 85 and 89 mmHg based on 2 or more properly measured seated BP readings on each of 2 or more office visits , patients were defined as dippers if their nocturnal BP fall was equal or greater than 10%, overdippers if greater than 20%, and nondippers if 0%–10%. The reverse dippers were regarded less than 0%. As supplementary, this research had found no overdippers and reverse dippers.The FDA and CE certified ambulatory blood pressure monitoring (ABPM)  , 5  and were compared by analysis of variance. Normal distribution was assessed through the Shapiro–Wilk test. The categorical variables between two groups were obtained through the p > 0.05) in ages, sex, FBG, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDLC). Dipper and nondipper were significantly higher than the normotensive in percentage of the family history of hypertension, BMI, and cholesterol. Furthermore, the nondipper group has significantly higher TG than both dipper and normotensive groups (p < 0.05)  .Average 24 h blood pressure in different types of SBP and DSB of both dipper and nondipper groups is higher than in the normotensive group. Coefficient variation of 24 h SBP of nondipper is higher than normotensive .2, dipper was 108 ± 13 g/m2, and normotensive was 98 ± 17 g/m2); furthermore, nondipper was significantly higher than dipper (p < 0.05).LVMI was higher in high-normal blood pressure patients compared with the normotensive ; what is more, coefficient of the variation value is also higher in the high-normal blood pressure group. According to the study of Parati [To the high-normal blood pressure patients, recent studies recommended that it is more efficient and reliable to monitor their blood pressure through ABPM , 14. Thrf Parati , the higf Parati , 18.Abnormalities in circadian blood pressure variability is one of the most important reasons that induces higher LVMI. Recent studies indicated that the high-normal blood pressure patients have abnormalities in circadian blood pressure variability due to the flowing reasons: first, autonomic nervous system function was dysregulation in the early stage of hypertension; hyperfunction of vagus nerve and imbalance of function of parasympathetic nervous during midnight will increase the nocturnal blood pressure and also decline circadian rhythm of BP . In the According to our research, abnormal circadian rhythm and higher BPV are found in the high-normal blood pressure group, and some indicators are even more similar to hypertensive level. Those changes would be reasons that induce the target organ damage, increase the LVMI, and lead the left ventricular hypertrophy. So, it is meaningful to test the high-normal blood pressure group through ABPM and apply intervention treatment that could decrease the target organs damage and prevent hypertension.After multiple relevant clinical confounding factors were adjusted, patients with dipper and nondipper high-normal blood pressure had higher LVMI. Abnormalities in circadian blood pressure variability may be associated with the left ventricular hypertrophy.


However, its relevance in critically ill patients is still under investigation. In this study we measured the association between ventriculo-arterial coupling and oxygen consumption (VOA), and ventricular elastances (EV), total indexed peripheral resistances were assessed before and after hemodynamic interventions. VO2 responsiveness was defined as VO2 increase >15% following the hemodynamic intervention. Ventriculo-arterial coupling was assessed measuring the EA/EV ratio by echocardiography. The left ventricle stroke work to pressure volume area ratio (SW/PVA) was also calculated.Sixty-one cardio-thoracic ICU patients  who received hemodynamic therapeutic interventions  were included. Arterial pressure, cardiac output, heart rate, arterial  coupling ratio with a median value of 1.9 (1.6–2.4). Most of those patients were classified as VO2 responders . Changes in VO2 were correlated with those of indexed total peripheral resistances, EA, EA/EV and cardiac output. EA/EV ratio predicted VO2 increase with an AUC of 0.76 [95% CI: 0.62–0.87]; p = 0.001. In principal component analyses, EA/EV and SW/PVA ratios were independently associated (p < 0.05) with VO2 response following interventions.In the overall cohort, 24 patients (39%) were VO2 responders were characterized by baseline high ventriculo-arterial coupling ratio due to high EA and low EV. Baseline EA/EV and SW/PVA ratios were associated with VO2 changes independently of the hemodynamic intervention used. These results underline the pathophysiological significance of measuring ventriculo-arterial coupling in patients with hemodynamic instability, as a potential therapeutic target.VO The lof EA/EV . The effof EA/EV .Cardiology studies have demonstrated that V-A coupling may represent a parameter that describes the energetic cost in particular when LV function is altered , 9. TherThe present study was designed to investigate the clinical relevance of V-A coupling in critically ill patients. We sought to analyse the effects of two types of interventions: fluid challenge or norepinephrine infusion on systemic oxygenation parameters (as indicators of cardiovascular efficacy) and on V-A coupling (as an indicator of cardiovascular efficiency).A/EV ratio and changes in VO2 upon treatment of hemodynamic instability following cardiac surgery. The second objectives were to compare V-A coupling and oxygenation-derived parameters  as predictor of VO2 changes following hemodynamic treatment.The main objective of this study was to investigate the relationship between EThe study's objectives and procedures were approved by the local independent Ethics Committee . All patients received written information and gave their verbal consent to participate. The present manuscript was drafted in compliance with the STROBE checklist for cohort studies .This observational cohort study was performed in a university-affiliated cardiothoracic ICU between 2015 and 2017. We included patients aged 18 or over, under controlled positive ventilation, with hemodynamic instability, for whom the clinician decided to perform a fluid challenge and/or start a norepinephrine infusion. The indications for fluid challenge were: (1) arterial hypotension, defined as systolic arterial pressure (SAP) below 90 mmHg and/or a mean arterial pressure (MAP) below 65 mmHg, and/or (2) stroke volume (SV) variation of more than 10%, and/or (3) clinical signs of hypoperfusion. In the present study, fluid challenge always consisted of a 10-min infusion of 500 ml of lactated Ringer's solution . The ind−1) were measured using transthoracic echocardiography performed with a commercially available machine  equipped with a S5-1 Sector Array Transducer. The echocardiographic parameters were averaged from five measurements (regardless of the respiratory cycle). EV was estimated at the bedside using the non-invasive single beat method described by Chen et al. * Pes * 0.9)) / (SV * ENd(test)). ENd(test) was obtained from a group-averaged normalized elastance curve value at this same time td (ENd(avg)), baseline LV ejection fraction (LVEF) and the ratio of diastolic to systolic arterial pressure (V in ten patients. CV was 7.7% ± 0.6 and LSC was 10.9% ± 0.8. EA was estimated by using the formula EA= end-systolic pressure (ESP = 0.9 * SAP)/SV  and cardiac output /SV . SAP wasmHg.ml−1 , 19. An 0)/2) and assumes that V0 is negligible when compared with ESV. We calculated total indexed peripheral resistance (TPRi) as TPRi = MAP-central venous pressure (CVP)/cardiac index (mmHg ml−1 m−2).The total energy generated by each cardiac contraction is called the “pressure-volume area” (PVA), which is the sum of the external mechanical work exerted during systole (SW) and the potential energy (PE) stored at the end of systole: PVA = SW + PE . The PVAWe recorded the ventilator settings  at baseline. All parameters were measured on arterial and central venous blood gases .−1 ideal body weight, and a positive end-expiratory pressure (PEEP) of 5–8 cm H2O, and sedated with Propofol , CVP, SV, CO, and arterial/venous oxygen content were measured at baseline.A/Ev ratio and VO2 response with a power of 0.8 and alpha error of 0.05. The variables' distribution was assessed using a D'Agostino-Pearson test. Data are expressed as the number, proportion (in percent), mean ± standard deviation (SD) or the median [interquartile range (IQR)], as appropriate. Patients were classified as VO2 responders or non-responders as a function of the effect of hemodynamic interventions  on VO2. VO2 response was defined as an increase of more than 15% in the VO2. The non-parametric Wilcoxon rank sum test, Student's paired t-test, Student's t-test, the Mann-Whitney test, and the Fisher's test were used to assess statistical significance, as appropriate. Correlations were tested using Pearson's or Spearman's rank test, as appropriate.In the absence of preliminary data, we designed an observational study with a convenience sample of 61 consecutive patients. Such size could enable to demonstrate a correlation (0.3–0.5) between E2 changes. A principal component analysis was carried out by including fourteen baseline variables. The VO2 changes following therapeutic interventions were included as a supplementary variable. Considering there were some differences between baseline characteristics between VO2 responders vs. non-responders in univariate, we performed a multivariate regression logistical model in order to determinate the independent adjusted associations. The conditions of validity of the multivariate model were checked, in order to have at least 5 responders for each variable included in the model. A receiver-operating characteristic (ROC) curve was established for the ability of ScVO2, CO2 gap, EV/EA ratio to predict an increase of more than 15% in VO2.Because we have analyzed several correlated hemodynamic and perfusion variables, we performed an exploratory principal component analysis to avoid collinearity. The principal component analysis transforms correlated variables into uncorrelated variables that may explain VOp < 0.05. R software (version 3.5.0) with FactoMineR package was used for all statistical analyses.The threshold for statistical significance was set to A/EV ratio of 1.9 (1.6–2.4) mainly related to abnormally low EV (1.1 (0.9–1.6)), as compared to preserved EA (2 (1.5–2.7)). In the overall population, 31 patients (48 %) were classified as VO2 responders. The percentage of VO2 responders did not differ between the two groups . Of the 6 patients with mitral regurgitation surgery, 2 were in the group of VO2 responders and 4 in the group of VO2 non responders .Of the 65 included patients, four were excluded , and so 2 responders had higher EA/EV ratio, and lower SW/PVA ratio and VO2 than VO2 non-responders , EA , EA/EV , CO , ScVO2 , TPRi . The baseline SW/PVA ratio was correlated with DO2 , VO2 , and gapCO2 .In the overall cohort, changes in VOA/EV was predictive of VO2 responsiveness, with an area under the curve (AUC) [95% confidence interval (95%CI)] of 0.76 . The best cut-off was 2.1 with a gray zone between 1.8 and 2.4. With an AUC [95%CI] of 0.72 [0.59–0.85] (p = 0.004), baseline ScVO2 was predictive of VO2 responsiveness. With an AUC [95%CI] of 0.44 [0.29–0.58] (p = 0.05), gapCO2 was not predictive of VO2 responsiveness. When analyzing patients separately for fluid challenge or norepinephrine infusion, baseline EA/EV was predictive of VO2 responsiveness in fluid challenge group (AUC: 0.77 [0.59–0.95] (p = 0.008) and norepinephrine group (AUC: 0.74 [0.56–0.93] (p = 0.045).Baseline E2, SW/PVA ratio, EA/EV ratio). Baseline EA/EV ratio  and ScVO2  were independently associated with VO2 responsiveness, but not the baseline LVEF  and SW/PVA ratio . When using the principal component analysis, the 3 first principal components explained 61% of the variance (2 changes were significantly associated with the first (r = 0.31) and the third component (r = 0.52). EA, EV, EA/EV, and SW/PVA ratio were variables included in components associated to VO2 changes.These results were confirmed by the multivariate regression model adjusted on differences at baseline  at baseline; (2) baseline EA/EV and SW/PVA ratios were associated with perfusion parameters and VO2 changes independently of the therapeutic intervention used.The main results of the present study are as follow: (1) most patients for whom fluid challenge or norepinephrine infusion increased VO2 responders have an increase in SV, CO and a decrease in TPRi. VO2 responder patients were uncoupled before interventions as they adapted to maintain tissue perfusion with a higher energetic cost for the same efficacy (preserving efficacy over efficiency). This was reflected by the lower EA/EV ratio in VO2-responders. Equally, VO2-responder patients had significantly lower SW/PVA values before hemodynamic intervention, which were associated to perfusion parameters. We demonstrated that the EA/EV ratio partly explains VO2 responsiveness and was independently associated with VO2 responsiveness. Both approaches credibly establish at least the statistical relevance of analyzing V-A coupling in patients with hemodynamic instability following cardiac surgery.When analyzing together fluid challenge or norepinephrine infusion, the only common profile is the increase in arterial pressure. VOA = EV   , 6, 21. nt study . Patientstudy  transmitted to the peripheral circulation . This tr2 and VO2 on the other in ICU patients  for which hemodynamic treatment may differ . More thstrategy . The norstrategy , 33. Tarstrategy  and possstrategy . Algoritstrategy , 35. As strategy , 37, the2 may be due to its effects on CO and DO2  patients, larger cohorts are required to perform a properly matching on different confounding factors. The clinical relevance of the relationship between V-A coupling and VO awaited .2 responders, V-A coupling was characterized by a high EA/EV ratio (due to high EA and low EV). Baseline EA/EV and SW/PVA ratios were associated with VO2 changes independently of the hemodynamic intervention used. Measuring V-A coupling may offer a new perspective of hemodynamic optimisation in the ICU by individualizing hemodynamic treatment and by analyzing both the efficacy and efficiency of hemodynamic interventions.In VOThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by . The patients/participants provided their written informed consent to participate in this study.SA, MN, and P-GG conceived the study, analyzed the data and drafted the manuscript. P-GG collected the data. DL, BP, and BB provided a critical review. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Electrophysiological diagnosis of cardiac autonomic neuropathy (CAN) is based on the evaluation of cardiovascular autonomic reflex tests (CARTs). CARTs are relatively time consuming and must be performed under standardized conditions. This study aimed to determine whether thermal quantitative sensory testing (TQST) can be used as a screening tool to identify patients with diabetes at a higher risk of CAN.Eighty‐five patients with diabetes and 49 healthy controls were included in the study. Neurological examination, CARTs, TQST, biochemical analyses, and neuropathy symptom questionnaires were performed.CAN was diagnosed in 46 patients with diabetes (54%). CAN‐positive patients with diabetes had significantly higher warm detection thresholds (WDT) and significantly lower cold detection thresholds (CDT) in all tested regions . CDT on the dorsum < 21.8°C in combination with CDT on the tibia < 23.15°C showed the best diagnostic ability in CAN prediction, with 97.4 % specificity, 60.9% sensitivity, 96.6% positive predictive value, and 67.3% negative predictive value.TQST can be used as a screening tool for CAN before CART. This study aimed to determine whether thermal quantitative sensory testing (TQST) can be used as a screening tool to identify patients with diabetes at a higher risk of cardiac autonomic neuropathy. Eighty‐five patients with diabetes were included in the study. Cold detection threshold (CDT) on the dorsum of the foot < 21.8°C in combination with CDT on the tibia < 23.15°C showed the best diagnostic ability in CAN prediction, with 97.4% specificity, 60.9% sensitivity, 96.6% positive predictive value, and 67.3% negative predictive value. TQST can be used as a screening tool for CAN before CART in patients with diabetes mellitus. In addition to distal symmetric peripheral neuropathy, CAN is one of the most common types of diabetic neuropathy  were published in the 1970s  and 52 age‐ and sex‐matched healthy controls were enrolled in this cross‐sectional study. All subjects provided signed informed consent. This study was approved by the local ethics committee. Subjects with other causes of somatic or autonomic neuropathy or serious cognitive impairment  were excluded from the study. Two patients with diabetes (T2DM) and three healthy controls were excluded from the study because of newly detected atrial fibrillation during the CARTs. Ultimately, 85 patients with diabetes (55 T1DM + 30 T2DM patients) and 49 healthy controls completed the study, and their data were analyzed. The main characteristics of the study subjects are summarized in Table A total of 87 patients with diabetes  and temperature sensation (TipTherm). Large nerve fiber function was assessed based on vibration thresholds using a calibrated 128‐Hz tuning fork, and tactile sensation was assessed with a 10‐g nylon Semmes‐Weinstein monofilament.2.3TQST was performed in all subjects. The thermal stimulator  was equipped with a 25 × 50 mm thermode (liquid‐cooled Peltier element) with a nonallergic silver contact surface. Cold detection threshold (CDT) and warm detection threshold (WDT) on the thenar eminence, tibia, and lateral aspect of the dorsum of the foot bilaterally were determined. A nonrandomized method of measuring reaction time, that is, the method of limits, was used as an investigative algorithm. The duration of the examination was approximately 20 min. Five values for warm perception and five values for cold perception were recorded in each tested region. The mean of these five values was used as the threshold. Previously published normative data to compare our values of thermal threshold values were used , Michigan neuropathy screening instrument examination (MNSIE), Utah early neuropathy scale (UENS), Survey of autonomic symptoms (SAS), and painDetect , and Valsalva ratio, were assessed. Blood pressure response during standing was considered abnormal when the diastolic blood pressure decreased by >10 mmHg or the systolic blood pressure decreased by >30 mmHg within 2 min after standing  under standardized conditions  or Fisher's exact test. To determine the thermal threshold with the best predictive value for identifying CAN‐positive/negative patients, ROC analysis was performed. The achieved test levels were adjusted for multiple comparisons using the Holm method. Adjusted test levels of <5% were considered statistically significant.Statistical analysis was performed using R package version 3.4.4 . Differences in continuous variables between the studied groups were tested using two‐sample tests. The 3n = 32; T2DM, n = 14). No statistically significant differences were found in the type and duration of diabetes between the CAN‐positive and CAN‐negative patients (p > .05). Compared to normative data, pathological values of CDT were found in 31 CAN‐positive and 8 CAN‐negative patients. Pathological values of WDT were found in 24 CAN‐positive and 6 CAN‐negative patients. The statement “pathological values of CDT and WDT” was determined if at least one abnormal value was measured in at least one tested region.Patients with diabetes were divided into CAN‐positive and CAN‐negative patients. The main clinical and laboratory parameters of the study groups are presented in Table p = .0020) and WDT (p = .0224).The difference between the number of diabetic patients with pathological thermal thresholds between CAN‐positive and CAN‐negative was statistically significant in CDT (p = .0398), tibia (p < .001), and lateral aspect of the dorsum of the foot (p < .001). WDT values were significantly higher in CAN‐positive patients on the thenar prominence (p = .0205), tibia (p = .0205), and lateral aspect of the dorsum of the foot (p < .001).Further, all measured values of CDT and WDT were compared in CAN‐positive and CAN‐negative patients with diabetes in more detail. CDT values were significantly lower in CAN‐positive patients on the thenar eminence , CDT measured on the tibia with the cut‐off value of 23.15°C , and WDT measured on the dorsum of the foot with the cut‐off value of 46.35°C  were tests with the best predictive value. The combination of more TQST parameters in more locations increased the specificity and positive predictive value. CDT on the dorsum of the foot <21.8°C in combination with CDT on the tibia <23.15°C showed the best diagnostic accuracy in the CAN prediction with 97.4% specificity, 60.9% sensitivity, 96.6% positive predictive value, and 67.3% negative predictive value. The results of TQST in predicting CAN in patients with diabetes are summarized in Table In addition to TQST, several biochemical metabolic parameters and questionnaires focused on neuropathic symptoms were also analyzed to identify other potential markers that could contribute to the pathophysiology of CAN in diabetes mellitus.p < .05) in the following variables: diastolic blood pressure (p < .001), albumin/creatinine ratio (p = .002), UENS score (p = .0228), MNSIQ score (p = .0018), and MNSIE score (p = .0025). All of the above variables had higher values in the CAN‐positive patients. The diagnostic accuracy for these variables in predicting CAN was not superior compared to TQST. The highest 80.4% sensitivity but low specificity of 61.5% showed the diastolic blood pressure with the cut‐off point of 76.5 mmHg. MNSIQ with the cut‐off value of 5.5 points was the questionnaire with the highest specificity of 94.9% but poor 50% sensitivity. Complete data are presented in Table p = .4932) and presence of distal symmetric polyneuropathy (p = .0968).Statistically significant differences were found between CAN‐positive and CAN‐negative patients (p > .05) between CAN‐positive and CAN‐negative patients was found in the following biochemical parameters: fasting blood glucose, glycosylated hemoglobin, triglycerides, cholesterol, low‐ and high‐density lipoprotein, plasma urea and creatinine, thyroid‐stimulating hormone, and free thyroxine.No statistically significant difference . Quantitative sensory testing of CDT in the lower extremities showed the best diagnostic ability to differentiate CAN‐positive from CAN‐negative patients. CDT on the dorsum of the foot <21.8°C in combination with CDT on the tibia <23.15°C can predict CAN with a very high specificity of 97.4% and a positive predictive value of 96.6%. This TQST combination showed a lower sensitivity of 60.9% and a negative predictive value of 67.3%, which means some patients with CDTs under these cut‐off values were evaluated as a false negative for the presence of CAN. Detection of a WDT value on the tibia >40.85°C with a high sensitivity of 85% and a moderate negative predictive value of 69% for CAN prediction can help.Further, CAN‐positive patients scored significantly higher on questionnaires describing somatic neuropathic symptoms such as MNSIQ, MNSIE, and UENS with a sensitivity up to 76% and specificity up to 94.9%. The fact is not surprising since both autonomic and sensory neuropathies are frequently combined  values and the presence of CAN. Similar results were published by Low et al. . ZillioxIn addition to TQST and questionnaires, significantly higher diastolic blood pressure values (cut‐off point 76.5 mmHg) and higher albumin/creatinine ratios (cut‐off point 1.009 g/mol) were measured in patients with CAN. Our results are congruent with previously published studies that demonstrated higher diastolic blood pressure values . The best diagnostic ability in the CAN prediction we found to be CDT on the dorsum of the foot and CDT on the tibia. The study confirmed that TQST can be used as screening tool to identify diabetic patients for further autonomic testing in clinical practice.The authors do not have any conflicts of interest to declare.https://publons.com/publon/10.1002/brb3.2506.The peer review history for this article is available at