Effects of anesthetic method on inflammatory response in patients with Parkinson’s disease: a randomized controlled study

Effects of anesthetic method on inflammatory response in patients with Parkinson’s disease: a randomized controlled study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Effects of anesthetic method on inflammatory response in patients with Parkinson’s disease: a randomized controlled study Won Jung Hwang, Min Ah Joo, Jin Joo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-22571/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Aug, 2020 Read the published version in BMC Anesthesiology → Version 1 posted 3 You are reading this latest preprint version Abstract Background The pathogenesis of Parkinson’s disease (PD) involves degeneration of dopaminergic neurons, which is influenced by innate and adaptive immunity. IL-17 is a characteristic cytokine secreted by Th17 cells, which acts as a powerful stimulator of neutrophil migration and infiltration and promotes the secretion of inflammatory cytokines. General anesthesia and surgical stress induce immune and inflammatory responses that activate the immunosuppressive mechanism in the perioperative period. The present study investigated changes in levels of inflammatory cytokines, such as IL-17, IL-1β, and TNF-α, in patients with PD undergoing general anesthesia with inhalational anesthetics or TIVA. Methods Adult patients, aged 40–75 years, scheduled for cerebral stimulator implantation were enrolled. Upon arrival at the operating theater, patients were allocated to the inhalational (I) or TIVA (T) group using block randomization. In group I, anesthesia was induced by tracheal intubation 1–2 min after intravenous administration of propofol (1–2 mg/kg) and rocuronium (0.6–1 mg/kg). Thereafter, anesthesia was maintained with 1–2 vol% sevoflurane, 0.01–0.2 kg/min remifentanil, and O2/air (FiO2 0.4). In group T, propofol (3–6 µg/mL), remifentanil (2–6 ng/mL), and rocuronium (0.6–1 mg/kg) were administered using target controlled infusion (TCI) for induction of anesthesia. Blood samples were obtained preoperatively (T0), 2 h after induction of anesthesia (T1), and 24 h after surgery (T2). IL-17, IL-1β, and TNF-α levels were evaluated by ELISA. Results Serum levels of IL-17 were elevated at T2 in group I compared to group T but the difference was not statistically significant. IL-1β tended to be greater in group I compared to group T, but the differences were not significant. (Fig. 3). TNF-α was slightly higher at all time points in group T and showed a tendency to increase at T2 in both groups, but this was not statistically significant (Fig. 4). Conclusions  TIVA may be useful for inhibiting neuroinflammation by inhibiting the increase in serum levels of IL-17 24 h after implantation surgery. Serum IL-17 level may be used as a biomarker for PD progression. TRIAL REGISTRATION: Clinical Research Information Service of Korea National Institute of Health (CRIS) Identification number: KCT0002061. Registered 25 October 2019 - Retrospectively registered, https://cris.nih.go.kr/cris/search/search_result_st01.jsp?seq=15125 Anesthesiology & Pain Medicine Parkinson’s disease Inhalational anesthetic Total intravenous anesthesia (TIVA) Inflammatory response Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Parkinson’s disease (PD) is a progressive central nervous system (CNS) movement disorder, and is the second most common inflammatory neurodegenerative disorder after Alzheimer’s disease [ 1 ]. About 2–3% of elderly people above 65 years old have PD [ 2 ]. The earliest symptoms are bradykinesia, resting tremor, rigidity, and impairment of balance. These motor symptoms are caused by a decrease in levels of the neurotransmitter dopamine, due to death of dopaminergic neurons in the substantia nigra [ 3 ]. This degeneration of dopaminergic neurons is accompanied by inflammatory changes in microglia (innate immunity) and infiltration of T lymphocytes (adaptive immunity) [ 4 ]. There have been a number of studies of the relations between PD and immunity, and Th17 cells play an important role in neurodegeneration in experimental models of PD [ 5 ]. In patients with PD, Th17 cell effector molecules are upregulated and the immune pathways of Th17 cells are activated. Th17 cells produce cytokines, such as IL-17, IL-21, IL-1β, and TNF-α, resulting in neuronal apoptosis [ 5 , 6 ]. IL-17 is a characteristic cytokine secreted by Th17 cells that acts as a powerful stimulator of neutrophil migration and infiltration and promotes the secretion of inflammatory cytokines, such as IL-1, TNF-α, and IL-6, by microglial cells [ 7 ]. These cytokines lead to neuronal cell death, resulting in neurodegeneration. General anesthesia and surgical stress induce immune and inflammatory responses that activate the immunosuppressive mechanism in the perioperative period [ 8 ]. Unlike inhalation anesthetics, propofol shows antioxidant activity that protects cells and tissues from toxic free radicals [ 9 , 10 ]. There has been a great deal of research on the relations between general anesthesia and immunity. Inhalational anesthetics have a greater immunosuppressive effect than total intravenous anesthesia (TIVA) using propofol. With the aging of the population, increasing numbers of elderly patients with PD are undergoing various types of surgery under general anesthesia [ 11 ]. However, there have been no studies on the effects of anesthetic method on inflammatory responses in patients with PD. The present study investigated changes in levels of inflammatory cytokines, such as IL-17, IL-1β, and TNF-α, in patients with PD undergoing general anesthesia with inhalational anesthetics or TIVA. Methods The protocol of this study adheres to CONSORT guidelines. Study population and ethical approval The study protocol was approved by the Institutional Review Board of Seoul St. Mary’s Hospital, The Catholic University of Korea (approval no. KC17RESI0365) and has been registered with the Clinical Research Information Service of Korea National Institute of Health (CRIS, identification number: KCT0002061). Each patient provided written and oral informed consent. Adult patients, aged 40–75 years, with American Society of Anesthesiologists (ASA) physical status class I or II and who were scheduled for cerebral stimulator implantation to control symptoms between June 2018 and December 2019 were enrolled in this randomized, prospective study. Patients with myocardial infarction or coronary artery disease aside from diabetes and hypertensive heart disease, patients with lung diseases, such as asthma or chronic obstructive pulmonary disease (COPD), with AST/ALT greater than normal, and with a medical history of hypersensitivity to inhalation anesthetics or propofol were excluded. Anesthetic management Patients were not allowed to eat and drink 8 h before surgery. Upon arrival at the operating theater, patients were allocated to the inhalational (I) or TIVA (T) group using block randomization. Basic monitoring, including ECG, noninvasive blood pressure (NIBP), pulse oximetry, and bispectral index (BIS), was used. Blood was drawn from peripheral blood vessels before induction of general anesthesia (T0). In group I, anesthesia was induced by tracheal intubation 1–2 min after intravenous administration of propofol (1–2 mg/kg) and rocuronium (0.6–1 mg/kg). Thereafter, anesthesia was maintained with 1–2 vol% sevoflurane, 0.01–0.2 kg/min remifentanil, and O2/air (FiO2 0.4). In group T, propofol (3–6 µg/mL), remifentanil (2–6 ng/mL), and rocuronium (0.6–1 mg/kg) were administered using target controlled infusion (TCI) for induction of anesthesia. After tracheal intubation, anesthesia was maintained with propofol (2–4 µg/mL), remifentanil (2–4 ng/mL), O2/air (FiO2 0.4). In both groups, the depth of anesthesia was adjusted to the anesthetic dose with a BIS of 40–60. Blood pressure and pulse were maintained at around 20% of the respective baseline. At the end of surgery, anesthetics were discontinued and sugammadex was used to reverse the muscle relaxant effect. At this time, blood was taken from the peripheral blood vessels (T1). Extubation was carried out when the patient’s breathing had returned sufficiently, and then the patient was moved to the recovery room. Blood was taken from peripheral blood vessels 24 h after surgery (T2). Cytokine analyses Blood samples were centrifuged at 1500 rpm for 10 min at room temperature. Serum was removed and stored in 200 µL aliquots at − 80 °C until assays were performed. Serum was dispensed onto coated ELISA plates. Levels of cytokines in the serum samples were determined by ELISA using the following kits in accordance with the manufacturer’s instructions: IL-1β, sensitivity: 6.5 pg/mL (ab46052; Abcam, Cambridge, MA); TNF-α, sensitivity: 4.32 pg/mL (181421; Abcam); IL-17, sensitivity: < 10 pg/mL (100556; Abcam). ELISA plates were analyzed using a microtiter plate reader (BioTek Instruments, Inc., Winooski, VT) at 450 nm after stopping the reaction. Data collection and statistical analyses For sample size calculation, IL-17 levels described in a previous animal study were used [ 12 ]. With a 10 pg/dL difference in mean value between groups and a standard deviation of 8, the sample size required at a significance level of 5% (two-sided α = 0.05) and a power of 80% (1 – β = 0.8) was 15 patients per group, taking a 10% dropout rate into consideration. All data were analyzed using SPSS (ver. 18.0; SPSS, Inc., Chicago, IL). Demographic data were compared using the χ2 test and t test as appropriate. Repeated-measures ANOVA was performed to compare the IOP and OPP between the groups, with group and time point as independent variables, after confirming the normality of the distribution with the Shapiro–Wilk test (p > 0.05). The interaction term was calculated with Bonferroni’s correction for repeated measures. In all analyses, p < 0.05 was taken to indicate statistical significance. Results A total of 30 patients were recruited for the study; two were excluded from data analyses (one in each group) due to low blood pressure maintained during surgery and loss to follow-up (Fig. 1 ). Demographic data and perioperative data are shown in Table 1 . There were no significant differences in preoperative baseline (T0) IL-17 level between groups I and T (675.6 ± 398.4 vs. 705.7 ± 312.7 pg/mL, respectively; p > 0.05). IL-17 did not show any increase at T1 in either group; it tended to increase at T2 in group I compared to group T (843 ± 384.1 vs. 695.5 ± 391.2 pg/mL, respectively; p > 0.05), but the difference was not statistically significant (Fig. 2 ). IL-1β tended to be greater in group I compared to group T, but the differences were not significant. (Fig. 3 ). TNF-α was slightly higher at all time points in group T and showed a tendency to increase at T2 in both groups, but this was not statistically significant (Fig. 4 ). Discussion Various studies have demonstrated that the pathogenesis of PD involves neuroinflammation, which is affected by both innate and adaptive immunity, and the levels of proinflammatory cytokines are elevated in PD patients [ 5 , 13 – 15 ]. Th17 cells are among the most important lymphocytes involved in degeneration of dopaminergic neurons in PD [ 5 ]. Th17 cells secrete the proinflammatory cytokine IL-17, which is commonly associated with allergic responses. IL-17 promotes the secretion of other cytokines, such as IL-1β and TNF-α, and plays a pivotal role in the early stages of inflammation. These cytokines bind to receptors on dopaminergic neurons, resulting in apoptosis [ 4 , 6 , 16 ]. To the best of our knowledge, this is the first study to investigate the effects of anesthetic method on inflammatory response in patients with PD. IL-17 at 24 h after surgery tended to increase under inhalational anesthesia, while it was maintained at the preoperative baseline level under TIVA. IL-1β and TNF-α also tended to increase at 24 h after surgery under inhalational anesthesia, but the effect was not significant. These results suggest that TIVA has advantages with regard to inhibition of neuroinflammation after surgery in PD patients despite its lack of statistical significance. Surgical stress and anesthesia induce inflammatory responses by disturbing the balance between pro- and antiinflammatory cytokines [ 8 ], which may result in aggravation of the neuroinflammatory response in PD patients. Previous studies have indicated that TIVA has superior effects in inhibiting inflammatory responses to inhalational anesthetics [ 9 , 17 – 19 ]. Shan et al. [ 20 ] reported that the inhalational anesthetic sevoflurane has a negative effect and aggravates the prognosis of PD in a Drosophila model. We attributed the lack of statistical significance in this study to the relatively short duration of surgery and the follow-up of only 24 h after surgery may not have been sufficient to reveal cytokine changes. A decline of immunity due to surgery and anesthesia occurs from roughly 2 h after induction of anesthesia, and the peak of immunosuppression occurs 3 days after surgery [ 8 ]. We obtained blood samples 2 h after induction of anesthesia when changes in the immune responses had just begun and 24 h after surgery when changes had not yet reached their peak. The baseline IL-17 level in this study was about 700 pg/mL. Sommer et al. [ 21 ] reported that IL-17 levels in PD patients were about 350 pg/mL, while they were below 50 pg/mL in controls. Resting tremor, rigidity, bradykinesia, and impairment of balance are characteristic motor symptoms of PD. Shan et al. [ 20 ] reported that impairment of locomotor abilities is aggravated with exposure to sevoflurane in a Drosophila PD model. Tuon et al. [ 12 ] reported that IL-17 levels decrease after physical training in an experimental mouse model of PD. Williams-Gray et al. [ 2 ] showed that serum levels of cytokines, such as IL-1β, TNF-α, and IL-10, are higher in PD patients than in age-matched non-PD controls; higher TNF-α levels are associated with faster rates of motor decline and higher IL-1β levels are associated with a faster rate of cognitive decline. These studies suggest that IL-17 and TNF-α are closely related to the motor symptoms of PD. Our cohort consisted of patients who had been diagnosed with PD for about 10 years and required cerebral stimulator implantation to manage motor symptoms that were not controlled by medications. These observations suggest that serum levels of IL-17 increase with the progression of PD. That is, neuroinflammation induced by Th-17 cells causing neuronal cell apoptosis may be an important factor in the progression of PD symptoms. Thus, serum IL-17 may be used as a biomarker for PD progression. However, our results did not reach statistical significance. As no similar clinical studies have been reported in the literature, we used the results from an experimental animal study for sample size calculation [ 12 ]. In that study, the authors analyzed the levels of IL-17 in the brain tissue of a mouse model of PD 24 h after the intervention. However, the baseline IL-17 level is different between mice and humans. Nevertheless, we believe that this study was worthwhile as a pilot study in that it determined the baseline serum level of IL-17 for use in future clinical studies on PD. In addition, we did not examine the motor symptoms before and after surgery in relation with cytokine changes. We selected PD patients undergoing brain stimulator implantation, and it would have been difficult to evaluate the motor symptoms before surgery due to the severity of PD and after surgery due to the stimulation. We intend to compare changes in short- and long-term motor symptoms in relation to cytokine changes in a future study. In conclusion, TIVA may be useful for inhibiting neuroinflammation by inhibiting the increase in serum levels of IL-17 24 h after implantation surgery. Serum IL-17 level may be used as a biomarker for PD progression since it was much higher in PD patients with severe motor symptoms. Further clinical trials to investigate the relationships between changes in cytokine levels and motor symptoms are needed. Abbreviations PD: Parkinson’s disease; CNS: Central nervous system; TIVA: Total intravenous anesthesia; ASA: American society of Anesthesiologists; BIS: Bispectral index Declarations Ethics approval and consent to participate The study protocol was approved by the Institutional Review Board of Seoul St. Mary’s Hospital, The Catholic University of Korea (approval no. KC17RESI0365) and has been registered with the Clinical Research Information Service of Korea National Institute of Health (CRIS, identification number: KCT0002061). Each patient provided written and oral informed consent. Consent for publication Not applicable Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interest The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results. Funding The authors wish to acknowledge the financial support of the Catholic Medical Center Research (S-2017-130001-0023). Authors’ Contributions WJH and JJ contributed study design. WJH, MAJ and JJ collected and analyzed data. WJH and JJ drafted the manuscript. WJH, MAJ and JJ made critical revisions of the manuscript. All authors read and approved the final analysis of the manuscript. Acknowledgements Not applicable Authors’ information Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea References Delenclos M, Jones DR, McLean PJ, Uitti RJ. Biomarkers in Parkinson’s disease: Advances and strategies. Parkinsonism Relat Disord. 2016;22(Suppl 1):106–10. Williams-Gray CH, Wijeyekoon R, Yarnall AJ, Lawson RA, Breen DP, Evans JR, et al. Serum immune markers and disease progression in an incident Parkinson’s disease cohort (ICICLE-PD). Mov Disord. 2016;31(7):995–1003. Schlachetzki JC, Winkler J. The innate immune system in Parkinson’s disease: A novel target promoting endogenous neuroregeneration. Neural Regen Res. 2015;10(5):704–6. Appel SH. CD4 + T cells mediate cytotoxicity in neurodegenerative diseases. J Clin Invest. 2009;119(1):13–5. Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL, Gendelman HE. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. J Immunol. 2010;184(5):2261–71. Appel SH, Beers DR, Henkel JS. T cell-microglial dialogue in Parkinson’s disease and amyotrophic lateral sclerosis: Are we listening? Trends Immunol. 2010;31(1):7–17. Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med. 2002;8(5):500–8. Coffey JC, Wang JH, Smith MJ, Bouchier-Hayes D, Cotter TG, Redmond HP. Excisional surgery for cancer cure: Therapy at a cost. Lancet Oncol. 2003;4(12):760–8. Schneemilch CE, Ittenson A, Ansorge S, Hachenberg T, Bank U. Effect of 2 anesthetic techniques on the postoperative proinflammatory and anti-inflammatory cytokine response and cellular immune function to minor surgery. J Clin Anesth. 2005;17(7):517–27. Mathy-Hartert M, Mouithys-Mickalad A, Kohnen S, Deby-Dupont G, Lamy M, Hans P. Effects of propofol on endothelial cells subjected to a peroxynitrite donor (SIN-1). Anaesthesia. 2000;55(11):1066–71. Garcia-Perez L, Linertova R, Lorenzo-Riera A, Vazquez-Diaz JR, Duque-Gonzalez B, Sarria-Santamera A. Risk factors for hospital readmissions in elderly patients: A systematic review. QJM. 2011;104(8):639–51. Tuon T, Souza PS, Santos MF, Pereira FT, Pedroso GS, Luciano TF, et al. Physical Training Regulates Mitochondrial Parameters and Neuroinflammatory Mechanisms in an Experimental Model of Parkinson’s Disease. Oxid Med Cell Longev. 2015;2015:261809. Brodacki B, Staszewski J, Toczylowska B, Kozlowska E, Drela N, Chalimoniuk M, et al. Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci Lett. 2008;441(2):158–62. Garcia-Esparcia P, Llorens F, Carmona M, Ferrer I. Complex deregulation and expression of cytokines and mediators of the immune response in Parkinson’s disease brain is region dependent. Brain Pathol. 2014;24(6):584–98. Lane EL, Soulet D, Vercammen L, Cenci MA, Brundin P. Neuroinflammation in the generation of post-transplantation dyskinesia in Parkinson’s disease. Neurobiol Dis. 2008;32(2):220–8. Tzartos JS, Craner MJ, Friese MA, Jakobsen KB, Newcombe J, Esiri MM, et al. IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain. Am J Pathol. 2011;178(2):794–802. Kushida A, Inada T, Shingu K. Enhancement of antitumor immunity after propofol treatment in mice. Immunopharmacol Immunotoxicol. 2007;29(3–4):477–86. Ren XF, Li WZ, Meng FY, Lin CF. Differential effects of propofol and isoflurane on the activation of T-helper cells in lung cancer patients. Anaesthesia. 2010;65(5):478–82. Mitsuhata H, Shimizu R, Yokoyama MM. Suppressive effects of volatile anesthetics on cytokine release in human peripheral blood mononuclear cells. Int J Immunopharmacol. 1995;17(6):529–34. Shan Z, Cai S, Zhang T, Kuang L, Wang Q, Xiu H, et al. Effects of sevoflurane on leucine-rich repeat kinase 2-associated Drosophila model of Parkinson’s disease. Mol Med Rep. 2015;11(3):2062–70. Sommer A, Marxreiter F, Krach F, Fadler T, Grosch J, Maroni M, et al. Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson’s Disease. Cell Stem Cell. 2019;24(6):1006. Tables Table 1. Patient data Group I Group T p -value Age (yrs) 71.2 ± 6.4 72.0 ± 6.8 0.987 Sex (M/F) 8 / 6 7 / 7 0.705 Height (cm) 160.6 ± 10.5 161.5 ± 6.7 0.784 Weight (kg) 60.5 ± 12.0 63.4 ± 13.5 0.541 Years after diagnosis of Parkinson’s disease 10.4 ± 6.8 9.5 ± 5.2 0.688 Blood loss (ml) 25.4 ± 16.9 27.9 ± 15.8 0.819 Crystalloid infused (ml) 544.3 ± 305.7 507.9 ± 206.7 0.715 Surgery time (min) 167.5 ± 77.0 177.6 ± 47.5 0.363 Anesthesia time (min) 190.9 ± 34.5 195.0 ± 35.5 0.678 Categorical variables are shown as numbers and other variables are shown as means ± standard deviation. Supplementary Files CONSORT2010Checklist.doc Cite Share Download PDF Status: Published Journal Publication published 01 Aug, 2020 Read the published version in BMC Anesthesiology → Version 1 posted Submission checks completed at journal 29 Apr, 2020 Editor assigned by journal 22 Apr, 2020 Editor invited by journal 21 Apr, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-22571","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":539064,"identity":"8d32a750-546a-4018-b48e-fbff072a4a5c","order_by":1,"name":"Won Jung Hwang","email":"","orcid":"","institution":"Seoul St. Mary's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Won","middleName":"Jung","lastName":"Hwang","suffix":""},{"id":539065,"identity":"14935ba4-2c6a-49f1-bc42-e11fc365a5c8","order_by":2,"name":"Min Ah Joo","email":"","orcid":"","institution":"Seoul St. Mary's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Min","middleName":"Ah","lastName":"Joo","suffix":""},{"id":539066,"identity":"183f2a41-6f5f-4866-8d91-96a263b9cef7","order_by":3,"name":"Jin Joo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYBACxmYgkWAgwcwPpJkZGCx4IOIHCGh5UGHDLtkAZksQ1gLW9uBMGr/BAYgWBoJamNt5DB8kth2WNj5++PnjggoJGf4G5ocfGM7cw+MwHmMDoBZjszNphs0zzkjwSBxgM5ZguFGMT4uZBFBLstkNBsNm3jYJHgMGBjMGhg8JBLXUb57B/hGqhf0bYS0JZ9KYDSR4YLbwAG25gU8LW7FBQoUNs8SZnMLZPCC/HOYpBhqCW4th/+GND3+AorL9+IbPPBU29vzt7Rs/fDiGR0sDhwGaEDANMODWwMAgz8D+AI/0KBgFo2AUjAIgAADdMk3moxXK5gAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-4260-9397","institution":"Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jin","middleName":"","lastName":"Joo","suffix":""}],"badges":[],"createdAt":"2020-04-11 11:25:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-22571/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-22571/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12871-020-01112-9","type":"published","date":"2020-08-01T12:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":1048920,"identity":"a300da60-4928-4667-932b-a5f72321d715","added_by":"auto","created_at":"2020-05-07 17:21:36","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":162595,"visible":true,"origin":"","legend":"Consort flow diagram","description":"","filename":"FIg.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-22571/v1/FIg.1.jpg"},{"id":1048921,"identity":"a325f65c-7453-49c5-808c-cf52967951a6","added_by":"auto","created_at":"2020-05-07 17:21:36","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":73272,"visible":true,"origin":"","legend":"Changes in IL-17.\nT0, preoperative baseline; 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T2, 24 h after surgery","description":"","filename":"Fig.4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-22571/v1/Fig.4.jpg"},{"id":13502090,"identity":"a8a561f4-3c0c-465f-9858-689e11f42120","added_by":"auto","created_at":"2021-09-16 23:13:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":450155,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-22571/v1/a59bee09-3bac-44d6-b607-6effc07be22d.pdf"},{"id":1048919,"identity":"31f3d432-679d-4042-b15e-aad67356e6b6","added_by":"auto","created_at":"2020-05-07 17:21:36","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":224256,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORT2010Checklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-22571/v1/CONSORT2010Checklist.doc"}],"financialInterests":"","formattedTitle":"Effects of anesthetic method on inflammatory response in patients with Parkinson’s disease: a randomized controlled study","fulltext":[{"header":"Background","content":" \u003cp\u003eParkinson\u0026rsquo;s disease (PD) is a progressive central nervous system (CNS) movement disorder, and is the second most common inflammatory neurodegenerative disorder after Alzheimer\u0026rsquo;s disease [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. About 2\u0026ndash;3% of elderly people above 65\u0026nbsp;years old have PD [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The earliest symptoms are bradykinesia, resting tremor, rigidity, and impairment of balance. These motor symptoms are caused by a decrease in levels of the neurotransmitter dopamine, due to death of dopaminergic neurons in the substantia nigra [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This degeneration of dopaminergic neurons is accompanied by inflammatory changes in microglia (innate immunity) and infiltration of T lymphocytes (adaptive immunity) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere have been a number of studies of the relations between PD and immunity, and Th17 cells play an important role in neurodegeneration in experimental models of PD [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In patients with PD, Th17 cell effector molecules are upregulated and the immune pathways of Th17 cells are activated. Th17 cells produce cytokines, such as IL-17, IL-21, IL-1β, and TNF-α, resulting in neuronal apoptosis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. IL-17 is a characteristic cytokine secreted by Th17 cells that acts as a powerful stimulator of neutrophil migration and infiltration and promotes the secretion of inflammatory cytokines, such as IL-1, TNF-α, and IL-6, by microglial cells [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. These cytokines lead to neuronal cell death, resulting in neurodegeneration.\u003c/p\u003e \u003cp\u003eGeneral anesthesia and surgical stress induce immune and inflammatory responses that activate the immunosuppressive mechanism in the perioperative period [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Unlike inhalation anesthetics, propofol shows antioxidant activity that protects cells and tissues from toxic free radicals [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. There has been a great deal of research on the relations between general anesthesia and immunity. Inhalational anesthetics have a greater immunosuppressive effect than total intravenous anesthesia (TIVA) using propofol. With the aging of the population, increasing numbers of elderly patients with PD are undergoing various types of surgery under general anesthesia [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, there have been no studies on the effects of anesthetic method on inflammatory responses in patients with PD. The present study investigated changes in levels of inflammatory cytokines, such as IL-17, IL-1β, and TNF-α, in patients with PD undergoing general anesthesia with inhalational anesthetics or TIVA.\u003c/p\u003e "},{"header":"Methods","content":" \u003cp\u003eThe protocol of this study adheres to CONSORT guidelines.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population and ethical approval\u003c/h2\u003e \u003cp\u003eThe study protocol was approved by the Institutional Review Board of Seoul St. Mary\u0026rsquo;s Hospital, The Catholic University of Korea (approval no. KC17RESI0365) and has been registered with the Clinical Research Information Service of Korea National Institute of Health (CRIS, identification number: KCT0002061). Each patient provided written and oral informed consent. Adult patients, aged 40\u0026ndash;75 years, with American Society of Anesthesiologists (ASA) physical status class I or II and who were scheduled for cerebral stimulator implantation to control symptoms between June 2018 and December 2019 were enrolled in this randomized, prospective study. Patients with myocardial infarction or coronary artery disease aside from diabetes and hypertensive heart disease, patients with lung diseases, such as asthma or chronic obstructive pulmonary disease (COPD), with AST/ALT greater than normal, and with a medical history of hypersensitivity to inhalation anesthetics or propofol were excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAnesthetic management\u003c/h2\u003e \u003cp\u003ePatients were not allowed to eat and drink 8\u0026nbsp;h before surgery. Upon arrival at the operating theater, patients were allocated to the inhalational (I) or TIVA (T) group using block randomization. Basic monitoring, including ECG, noninvasive blood pressure (NIBP), pulse oximetry, and bispectral index (BIS), was used. Blood was drawn from peripheral blood vessels before induction of general anesthesia (T0). In group I, anesthesia was induced by tracheal intubation 1\u0026ndash;2\u0026nbsp;min after intravenous administration of propofol (1\u0026ndash;2\u0026nbsp;mg/kg) and rocuronium (0.6\u0026ndash;1\u0026nbsp;mg/kg). Thereafter, anesthesia was maintained with 1\u0026ndash;2\u0026nbsp;vol% sevoflurane, 0.01\u0026ndash;0.2\u0026nbsp;kg/min remifentanil, and O2/air (FiO2 0.4). In group T, propofol (3\u0026ndash;6\u0026nbsp;\u0026micro;g/mL), remifentanil (2\u0026ndash;6\u0026nbsp;ng/mL), and rocuronium (0.6\u0026ndash;1\u0026nbsp;mg/kg) were administered using target controlled infusion (TCI) for induction of anesthesia. After tracheal intubation, anesthesia was maintained with propofol (2\u0026ndash;4\u0026nbsp;\u0026micro;g/mL), remifentanil (2\u0026ndash;4\u0026nbsp;ng/mL), O2/air (FiO2 0.4). In both groups, the depth of anesthesia was adjusted to the anesthetic dose with a BIS of 40\u0026ndash;60. Blood pressure and pulse were maintained at around 20% of the respective baseline. At the end of surgery, anesthetics were discontinued and sugammadex was used to reverse the muscle relaxant effect. At this time, blood was taken from the peripheral blood vessels (T1). Extubation was carried out when the patient\u0026rsquo;s breathing had returned sufficiently, and then the patient was moved to the recovery room. Blood was taken from peripheral blood vessels 24\u0026nbsp;h after surgery (T2).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eCytokine analyses\u003c/h2\u003e \u003cp\u003eBlood samples were centrifuged at 1500\u0026nbsp;rpm for 10\u0026nbsp;min at room temperature. Serum was removed and stored in 200\u0026nbsp;\u0026micro;L aliquots at \u0026minus;\u0026thinsp;80\u0026nbsp;\u0026deg;C until assays were performed. Serum was dispensed onto coated ELISA plates. Levels of cytokines in the serum samples were determined by ELISA using the following kits in accordance with the manufacturer\u0026rsquo;s instructions: IL-1β, sensitivity: 6.5\u0026nbsp;pg/mL (ab46052; Abcam, Cambridge, MA); TNF-α, sensitivity: 4.32\u0026nbsp;pg/mL (181421; Abcam); IL-17, sensitivity: \u0026lt; 10\u0026nbsp;pg/mL (100556; Abcam). ELISA plates were analyzed using a microtiter plate reader (BioTek Instruments, Inc., Winooski, VT) at 450\u0026nbsp;nm after stopping the reaction.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData collection and statistical analyses\u003c/h2\u003e \u003cp\u003eFor sample size calculation, IL-17 levels described in a previous animal study were used [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. With a 10\u0026nbsp;pg/dL difference in mean value between groups and a standard deviation of 8, the sample size required at a significance level of 5% (two-sided α\u0026thinsp;=\u0026thinsp;0.05) and a power of 80% (1 \u0026ndash; β\u0026thinsp;=\u0026thinsp;0.8) was 15 patients per group, taking a 10% dropout rate into consideration. All data were analyzed using SPSS (ver. 18.0; SPSS, Inc., Chicago, IL). Demographic data were compared using the χ2 test and t test as appropriate. Repeated-measures ANOVA was performed to compare the IOP and OPP between the groups, with group and time point as independent variables, after confirming the normality of the distribution with the Shapiro\u0026ndash;Wilk test (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The interaction term was calculated with Bonferroni\u0026rsquo;s correction for repeated measures. In all analyses, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was taken to indicate statistical significance.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":"\u003cp\u003eA total of 30 patients were recruited for the study; two were excluded from data analyses (one in each group) due to low blood pressure maintained during surgery and loss to follow-up (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Demographic data and perioperative data are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eThere were no significant differences in preoperative baseline (T0) IL-17 level between groups I and T (675.6\u0026thinsp;\u0026plusmn;\u0026thinsp;398.4 vs. 705.7\u0026thinsp;\u0026plusmn;\u0026thinsp;312.7\u0026nbsp;pg/mL, respectively; p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). IL-17 did not show any increase at T1 in either group; it tended to increase at T2 in group I compared to group T (843\u0026thinsp;\u0026plusmn;\u0026thinsp;384.1 vs. 695.5\u0026thinsp;\u0026plusmn;\u0026thinsp;391.2\u0026nbsp;pg/mL, respectively; p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), but the difference was not statistically significant (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eIL-1\u0026beta; tended to be greater in group I compared to group T, but the differences were not significant. (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). TNF-\u0026alpha; was slightly higher at all time points in group T and showed a tendency to increase at T2 in both groups, but this was not statistically significant (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":" \u003cp\u003eVarious studies have demonstrated that the pathogenesis of PD involves neuroinflammation, which is affected by both innate and adaptive immunity, and the levels of proinflammatory cytokines are elevated in PD patients [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Th17 cells are among the most important lymphocytes involved in degeneration of dopaminergic neurons in PD [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Th17 cells secrete the proinflammatory cytokine IL-17, which is commonly associated with allergic responses. IL-17 promotes the secretion of other cytokines, such as IL-1β and TNF-α, and plays a pivotal role in the early stages of inflammation. These cytokines bind to receptors on dopaminergic neurons, resulting in apoptosis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, this is the first study to investigate the effects of anesthetic method on inflammatory response in patients with PD. IL-17\u0026nbsp;at 24\u0026nbsp;h after surgery tended to increase under inhalational anesthesia, while it was maintained at the preoperative baseline level under TIVA. IL-1β and TNF-α also tended to increase at 24\u0026nbsp;h after surgery under inhalational anesthesia, but the effect was not significant. These results suggest that TIVA has advantages with regard to inhibition of neuroinflammation after surgery in PD patients despite its lack of statistical significance. Surgical stress and anesthesia induce inflammatory responses by disturbing the balance between pro- and antiinflammatory cytokines [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], which may result in aggravation of the neuroinflammatory response in PD patients. Previous studies have indicated that TIVA has superior effects in inhibiting inflammatory responses to inhalational anesthetics [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Shan et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] reported that the inhalational anesthetic sevoflurane has a negative effect and aggravates the prognosis of PD in a Drosophila model. We attributed the lack of statistical significance in this study to the relatively short duration of surgery and the follow-up of only 24\u0026nbsp;h after surgery may not have been sufficient to reveal cytokine changes. A decline of immunity due to surgery and anesthesia occurs from roughly 2\u0026nbsp;h after induction of anesthesia, and the peak of immunosuppression occurs 3 days after surgery [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. We obtained blood samples 2\u0026nbsp;h after induction of anesthesia when changes in the immune responses had just begun and 24\u0026nbsp;h after surgery when changes had not yet reached their peak.\u003c/p\u003e \u003cp\u003eThe baseline IL-17 level in this study was about 700\u0026nbsp;pg/mL. Sommer et al. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] reported that IL-17 levels in PD patients were about 350\u0026nbsp;pg/mL, while they were below 50\u0026nbsp;pg/mL in controls. Resting tremor, rigidity, bradykinesia, and impairment of balance are characteristic motor symptoms of PD. Shan et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] reported that impairment of locomotor abilities is aggravated with exposure to sevoflurane in a Drosophila PD model. Tuon et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] reported that IL-17 levels decrease after physical training in an experimental mouse model of PD. Williams-Gray et al. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] showed that serum levels of cytokines, such as IL-1β, TNF-α, and IL-10, are higher in PD patients than in age-matched non-PD controls; higher TNF-α levels are associated with faster rates of motor decline and higher IL-1β levels are associated with a faster rate of cognitive decline. These studies suggest that IL-17 and TNF-α are closely related to the motor symptoms of PD. Our cohort consisted of patients who had been diagnosed with PD for about 10\u0026nbsp;years and required cerebral stimulator implantation to manage motor symptoms that were not controlled by medications. These observations suggest that serum levels of IL-17 increase with the progression of PD. That is, neuroinflammation induced by Th-17 cells causing neuronal cell apoptosis may be an important factor in the progression of PD symptoms. Thus, serum IL-17 may be used as a biomarker for PD progression.\u003c/p\u003e \u003cp\u003eHowever, our results did not reach statistical significance. As no similar clinical studies have been reported in the literature, we used the results from an experimental animal study for sample size calculation [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In that study, the authors analyzed the levels of IL-17 in the brain tissue of a mouse model of PD 24\u0026nbsp;h after the intervention. However, the baseline IL-17 level is different between mice and humans. Nevertheless, we believe that this study was worthwhile as a pilot study in that it determined the baseline serum level of IL-17 for use in future clinical studies on PD. In addition, we did not examine the motor symptoms before and after surgery in relation with cytokine changes. We selected PD patients undergoing brain stimulator implantation, and it would have been difficult to evaluate the motor symptoms before surgery due to the severity of PD and after surgery due to the stimulation. We intend to compare changes in short- and long-term motor symptoms in relation to cytokine changes in a future study.\u003c/p\u003e \u003cp\u003eIn conclusion, TIVA may be useful for inhibiting neuroinflammation by inhibiting the increase in serum levels of IL-17 24\u0026nbsp;h after implantation surgery. Serum IL-17 level may be used as a biomarker for PD progression since it was much higher in PD patients with severe motor symptoms. Further clinical trials to investigate the relationships between changes in cytokine levels and motor symptoms are needed.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003ePD: Parkinson\u0026rsquo;s disease; CNS: Central nervous system; TIVA: Total intravenous anesthesia; ASA: American society of Anesthesiologists; BIS: Bispectral index\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Institutional Review Board of Seoul St. Mary\u0026rsquo;s Hospital, The Catholic University of Korea (approval no. KC17RESI0365) and has been registered with the Clinical Research Information Service of Korea National Institute of Health (CRIS, identification number: KCT0002061). Each patient provided written and oral informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors wish to acknowledge the financial support of the Catholic Medical Center Research (S-2017-130001-0023).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWJH and JJ contributed study design. WJH, MAJ and JJ collected and analyzed data. WJH and JJ drafted the manuscript. WJH, MAJ and JJ made critical revisions of the manuscript. All authors read and approved the final analysis of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Anesthesiology and Pain Medicine, Seoul St. Mary\u0026rsquo;s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e \u003cspan\u003eDelenclos M, Jones DR, McLean PJ, Uitti RJ. Biomarkers in Parkinson\u0026rsquo;s disease: Advances and strategies. 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QJM. 2011;104(8):639\u0026ndash;51.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eTuon T, Souza PS, Santos MF, Pereira FT, Pedroso GS, Luciano TF, et al. Physical Training Regulates Mitochondrial Parameters and Neuroinflammatory Mechanisms in an Experimental Model of Parkinson\u0026rsquo;s Disease. Oxid Med Cell Longev. 2015;2015:261809.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eBrodacki B, Staszewski J, Toczylowska B, Kozlowska E, Drela N, Chalimoniuk M, et al. Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci Lett. 2008;441(2):158\u0026ndash;62.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eGarcia-Esparcia P, Llorens F, Carmona M, Ferrer I. Complex deregulation and expression of cytokines and mediators of the immune response in Parkinson\u0026rsquo;s disease brain is region dependent. 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Differential effects of propofol and isoflurane on the activation of T-helper cells in lung cancer patients. Anaesthesia. 2010;65(5):478\u0026ndash;82.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eMitsuhata H, Shimizu R, Yokoyama MM. Suppressive effects of volatile anesthetics on cytokine release in human peripheral blood mononuclear cells. Int J Immunopharmacol. 1995;17(6):529\u0026ndash;34.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eShan Z, Cai S, Zhang T, Kuang L, Wang Q, Xiu H, et al. Effects of sevoflurane on leucine-rich repeat kinase 2-associated Drosophila model of Parkinson\u0026rsquo;s disease. Mol Med Rep. 2015;11(3):2062\u0026ndash;70.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eSommer A, Marxreiter F, Krach F, Fadler T, Grosch J, Maroni M, et al. Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson\u0026rsquo;s Disease. Cell Stem Cell. 2019;24(6):1006.\u003c/span\u003e \u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 32px; color: rgb(0, 0, 0); font-size: 10px; font-family: Verdana, Geneva, sans-serif;\"\u003eTable 1.\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003ePatient data\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" style=\"border-collapse: collapse;border: none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 112.7pt;border-top-width: 1pt;border-style: solid none;border-top-color: windowtext;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 112.7pt;border-top-width: 1pt;border-style: solid none;border-top-color: windowtext;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 32px;\"\u003eGroup I\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 112.7pt;border-top-width: 1pt;border-style: solid none;border-top-color: windowtext;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 32px;\"\u003eGroup T\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.7pt;border-top-width: 1pt;border-style: solid none;border-top-color: windowtext;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style=\"line-height: 32px;\"\u003ep\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 32px;\"\u003e-value\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 112.7pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003eAge (yrs)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e71.2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e6.4\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e72.0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e6.8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.7pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e0.987\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 112.7pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003eSex (M/F)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e/\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e6\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e7\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e/\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e7\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.7pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e0.705\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 112.7pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003eHeight (cm)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e160.6\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e10.5\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e161.5\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e6.7\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.7pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e0.784\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 112.7pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003eWeight (kg)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e60.5\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e12.0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e63.4\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e13.5\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.7pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e0.541\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 112.7pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003eYears after diagnosis of Parkinson\u0026rsquo;s disease\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e10.4\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e6.8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e9.5\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e5.2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.7pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e0.688\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 112.7pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003eBlood loss (ml)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e25.4\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e16.9\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e27.9\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e15.8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.7pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e0.819\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 112.7pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003eCrystalloid infused (ml)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e544.3\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e305.7\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e507.9\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e206.7\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.7pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e0.715\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 112.7pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003eSurgery time 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rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e77.0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e177.6\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border: none;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; 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0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e0.363\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 112.7pt;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003eAnesthesia time (min)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e190.9\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e34.5\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e195.0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.55pt;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e \u0026plusmn; \u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.6pt;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"8.333333333333334%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e35.5\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.7pt;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0in 5.4pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-size:16px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 10px;\"\u003e\u003cspan style=\"line-height: 32px;\"\u003e0.678\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin: 0in 0in 0.0001pt;line-height: 32px;font-family: \"Times New Roman\", serif;text-align: left;'\u003e\u003cspan style=\"line-height: 32px; color: rgb(0, 0, 0); font-size: 10px; font-family: Verdana, Geneva, sans-serif;\"\u003eCategorical variables are shown as numbers and other variables are shown as means \u0026plusmn; standard deviation. \u003c/span\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-anesthesiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bane","sideBox":"Learn more about [BMC Anesthesiology](http://bmcanesthesiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bane","title":"BMC Anesthesiology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Parkinson’s disease, Inhalational anesthetic, Total intravenous anesthesia (TIVA), Inflammatory response ","lastPublishedDoi":"10.21203/rs.3.rs-22571/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-22571/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\u003cp\u003eThe pathogenesis of Parkinson’s disease (PD) involves degeneration of dopaminergic neurons, which is influenced by innate and adaptive immunity. IL-17 is a characteristic cytokine secreted by Th17 cells, which acts as a powerful stimulator of neutrophil migration and infiltration and promotes the secretion of inflammatory cytokines. General anesthesia and surgical stress induce immune and inflammatory responses that activate the immunosuppressive mechanism in the perioperative period. The present study investigated changes in levels of inflammatory cytokines, such as IL-17, IL-1β, and TNF-α, in patients with PD undergoing general anesthesia with inhalational anesthetics or TIVA.\u003c/p\u003e\u003cp\u003eMethods\u003c/p\u003e\u003cp\u003eAdult patients, aged 40–75 years, scheduled for cerebral stimulator implantation were enrolled. Upon arrival at the operating theater, patients were allocated to the inhalational (I) or TIVA (T) group using block randomization. In group I, anesthesia was induced by tracheal intubation 1–2\u0026nbsp;min after intravenous administration of propofol (1–2\u0026nbsp;mg/kg) and rocuronium (0.6–1\u0026nbsp;mg/kg). Thereafter, anesthesia was maintained with 1–2\u0026nbsp;vol% sevoflurane, 0.01–0.2\u0026nbsp;kg/min remifentanil, and O2/air (FiO2 0.4). In group T, propofol (3–6\u0026nbsp;µg/mL), remifentanil (2–6\u0026nbsp;ng/mL), and rocuronium (0.6–1\u0026nbsp;mg/kg) were administered using target controlled infusion (TCI) for induction of anesthesia. Blood samples were obtained preoperatively (T0), 2\u0026nbsp;h after induction of anesthesia (T1), and 24\u0026nbsp;h after surgery (T2). IL-17, IL-1β, and TNF-α levels were evaluated by ELISA.\u003c/p\u003e\u003cp\u003eResults\u003c/p\u003e\u003cp\u003eSerum levels of IL-17 were elevated at T2 in group I compared to group T but the difference was not statistically significant. IL-1β tended to be greater in group I compared to group T, but the differences were not significant. (Fig.\u0026nbsp;3). TNF-α was slightly higher at all time points in group T and showed a tendency to increase at T2 in both groups, but this was not statistically significant (Fig.\u0026nbsp;4).\u003c/p\u003e\u003cp\u003eConclusions\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cspan class=\"ql-cursor\"\u003e\u003c/span\u003e\u003c/strong\u003eTIVA may be useful for inhibiting neuroinflammation by inhibiting the increase in serum levels of IL-17 24\u0026nbsp;h after implantation surgery. Serum IL-17 level may be used as a biomarker for PD progression.\u003c/p\u003e\u003cp\u003eTRIAL REGISTRATION:\u003c/p\u003e\u003cp\u003eClinical Research Information Service of Korea National Institute of Health (CRIS) Identification number: KCT0002061. Registered 25 October 2019 - Retrospectively registered, https://cris.nih.go.kr/cris/search/search_result_st01.jsp?seq=15125\u003c/p\u003e","manuscriptTitle":"Effects of anesthetic method on inflammatory response in patients with Parkinson’s disease: a randomized controlled study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-05-07 17:21:35","doi":"10.21203/rs.3.rs-22571/v1","editorialEvents":[{"type":"communityComments","content":1},{"type":"checksComplete","content":"","date":"2020-04-29T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-04-22T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-04-21T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-anesthesiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bane","sideBox":"Learn more about [BMC Anesthesiology](http://bmcanesthesiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bane","title":"BMC Anesthesiology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"06a5efc6-0d17-41d5-ad69-a880c7d97432","owner":[],"postedDate":"May 7th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":95608,"name":"Anesthesiology \u0026 Pain Medicine"}],"tags":[],"updatedAt":"2020-08-02T15:01:05+00:00","versionOfRecord":{"articleIdentity":"rs-22571","link":"https://doi.org/10.1186/s12871-020-01112-9","journal":{"identity":"bmc-anesthesiology","isVorOnly":false,"title":"BMC Anesthesiology"},"publishedOn":"2020-08-01 12:00:00","publishedOnDateReadable":"August 1st, 2020"},"versionCreatedAt":"2020-05-07 17:21:35","video":"","vorDoi":"10.1186/s12871-020-01112-9","vorDoiUrl":"https://doi.org/10.1186/s12871-020-01112-9","workflowStages":[]},"version":"v1","identity":"rs-22571","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-22571","identity":"rs-22571","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}