{"paper_id":"033bd9e8-56c0-41b9-87d0-a6c82ae3766c","body_text":"The Effects of Protective Ventilation on the Production of Endogenous Melatonin and Prognosis in Patients Undergoing Esophageal Cancer Surgery: A Prospective Randomized Double-Blind 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 The Effects of Protective Ventilation on the Production of Endogenous Melatonin and Prognosis in Patients Undergoing Esophageal Cancer Surgery: A Prospective Randomized Double-Blind Controlled Study Lixia Wang, Jun Li, Yuting Huang, Yan Zhu, Qiying Shen, Hongyun Zou, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-52115/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background: Exogenous melatonin exerts a similar effect to protective ventilation on attenuating ventilator-induced lung injury (VILI) by inhibiting NLRP3 inflammasome activation in mouse model. However, the effect of protective ventilation on the production of endogenous melatonin and prognosis in patients undergoing esophageal cancer surgery remains unknown. In this study, we aimed to reveal the effects of protective ventilation on the production of endogenous melatonin, interleukin (IL)-1β, IL-18 and major complications in patients undergoing esophageal cancer surgery. Methods: Eight-eight patients were randomized to receive “conventional” ventilation (Vt=10 mL/kg) or lung protective ventilation [Vt=5 mL/kg along with 5 cm of H 2 O positive end-expiratory pressure (PEEP)]. IL-1β, IL-18 and melatonin levels in bronchoalveolar lavage fluid (BALF) and serum were measured. Respiratory variables and outcomes were evaluated. Results: Lung protective ventilation decreased the peak airway pressure (Ppeak), plateau airway pressure (Pplat) and driving pressure (ΔP) compared with the “conventional” ventilation group. Lung protective ventilation inhibited polymorphonuclear (PMN) cells invasion into the BALF (P=0.000). Likewise, lung protective ventilation suppressed alveolar and serum IL-1β and IL-18 secretion after mechanical ventilation. Furthermore, lung protective ventilation resulted in a decrease in the inhibition of endogenous MT production compared to “conventional” ventilation (P=0.000). In addition, lung protective ventilation reduced the incidence of postoperative pulmonary complications (P=0.04) and the rate of major postoperative complications (P=0.023). Conclusions: Taken together, lung protective ventilation for esophageal cancer surgery suppressed the secretion of IL-1β, IL-18 and restored the endogenous melatonin level. Meanwhile, lung protective ventilation improved postoperative outcomes after esophageal cancer surgery. Trial registration: The Chinese Clinical Trial Registry, ChiCTR1900026190. Registered 25 September 2019, http://www.chictr.org.cn/edit.aspx?pid=34677&htm=4 Anesthesiology & Pain Medicine ventilator-induced lung injury one-lung ventilation NLRP3 inflammasome endogenous melatonin inflammation. Figures Figure 1 Figure 2 Figure 3 Background One-lung ventilation (OLV) is required for esophageal cancer and can contribute to the surgical field [ 1 ]. However, inappropriate ventilation modes may cause or augment acute lung injury, which is known as ventilator-induced lung injury (VILI) [ 2 ]. Lung protective ventilation [low tidal volume + positive end-expiratory pressure (PEEP)] was shown to achieve good clinical effects and protect against VILI [ 3 , 4 ]. Furthermore, clinical studies have demonstrated that lung protective ventilation induced an immune response with lower concentrations of inflammatory mediators than that of “conventional” ventilation [ 5 ]. Therefore, further studies of the effect of lung protective ventilation on the pulmonary immune response are essential to prevent VILI. Increasing studies have shown that OLV may lead to proinflammatory cytokine release and inflammatory signaling pathway activation [ 5 – 8 ]. Overdistension in ventilated lungs followed by compression of alveolar vessels initiates a robust release of proinflammatory cytokines, such as interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-a, in bronchoalveolar lavage fluid (BALF) [ 5 , 9 ]. These proinflammatory cytokines are important chemotactic factors for polymorphonuclear (PMN) cells [ 10 ]. Excessive PMN cell aggregation will amplify the inflammatory cascade. Furthermore, a recent study showed that in mouse alveolar macrophages, Nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome activation contributes to the development of VILI [ 11 ]. Melatonin (N-acetyl-5-methoxytryptamine, MT), which is mainly secreted in the pineal gland, has well-documented anti-inflammatory and immunomodulatory functions [ 12 , 13 ]. Early preliminary studies have shown that exogenous MT ameliorates VILI by increasing the anti-inflammatory response [ 14 ]. Recently, Zhang et al. demonstrated that exogenous MT inhibited NLRP3 inflammasome activation in mice with acute lung injury [ 15 ]. However, researchers have not determined whether lung protective ventilation affects NLRP3 inflammasome-related inflammatory cytokine and endogenous melatonin production in patients. Our study aimed to investigate the effects of lung protective ventilation on NLRP3 inflammasome-related inflammatory cytokine and endogenous MT secretion in patients undergoing video-assisted thoracoscopic esophagectomy (VATS). In addition, the effect of lung protective ventilation on postoperative complications was also investigated. Materials And Methods Study Design Patients scheduled for elective VATS at the First Affiliated Hospital of Anhui Medical University (Anhui, China) were included in the study. The study protocol had received prior approval from the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (No. 20190385), and this trial was registered in the Chinese Clinical Trial Registry (No. ChiCTR1900026190). Before participation in the study, all patients provided informed consent. Study Population Patients with esophageal cancer who were treated at our hospital were considered for enrollment. The inclusion criteria were as follows: American Society of Anesthesiologists (ASA) physical status I - Ⅲ, requirement for OLV during operation, and aged 45–77 years. Exclusion criteria were preexisting hypoxemia, diagnosed major obstructive or restrictive pulmonary disease [preoperative forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) <70% of the predicted value], pulmonary infection before surgery, body mass index (BMI) of less than 20 or more than 35, and use of immune modulators. Randomization and Blinding The randomized numbers were generated by a research coordinator using block sizes on a 1:1 ratio. This ensured that each group had an equal number of subjects. Then, the research coordinator sealed the numbers in opaque envelopes. Before mechanical ventilation, the anesthesia assistant opened the envelopes, set the breathing parameters and covered the breathing parameters using opaque paper. The anesthesia assistant did not participate in the next study. One anesthesiologist collected the specimens, and another anesthesiologist recorded the breathing parameters. Both physicians were blinded to the allocation. Study Protocol Standard monitoring devices were applied after admission to the operating room. Before induction of anesthesia, an artery catheter was inserted into the left radial artery. Anesthesia induction was performed with 2.0-2.5 mg/kg propofol, 0.02-0.06 mg/kg midazolam, 0.4-0.6 µg/kg sufentanil and 0.6-0.9 mg/kg rocuronium. 3 min after assisted breathing, a double-lumen endotracheal tube (Broncho-Cath ® 35 F or 37 F; Covidien, Ireland) was inserted into the left main bronchus. Anesthesia was maintained with 50–100 µg/kg/min of propofol, 0.1–1 µg/kg/min of remifentanil and 5.0–10.0 µg/kg/min of rocuronium to maintain the proper depth of anesthesia (BIS 40–60). A forced-air warming system (3M Company, Shanghai, China) was used to keep the patients warm. After intubation, the patients were randomly divided into 2 groups. In the control group (group A), patients received volume controlled mechanical ventilation with a tidal volume of 10 mL/kg of ideal body weight (IBW). In the lung protective ventilation group (group B), lung protective ventilation with a low tidal volume (Vt=5 mL/kg IBW) and 5 cm H 2 O PEEP was chosen. After 15 minutes, all patients were turned to the left lateral position and OLV was initiated. During OLV, the ventilation mode was not changed except the plateau airway pressure (Pplat) exceeded 30 cmH 2 O. If the Pplat exceeded 30 cmH 2 O, the tidal volume was decreased and this patient discontinued the experiment. With both two-lung ventilation (TLV) and OLV, mechanical ventilation was performed with an inspiratory to expiratory ratio of 1:2, and an appropriate respiratory rate to maintain an end-tidal CO 2 (ETCO 2 ) below 45 mmHg. All surgeries were always performed at 8:30 in the morning. Observational Indexes Peak airway pressure (Ppeak), Pplat, respiratory rate and blood gas analyses were evaluated at two stages: during TLV before surgery and 30 minutes after OLV. Furthermore, the driving pressure (ΔP) was recorded. ΔP was defined and calculated as follows: ΔP=Pplat–PEEP [16]. The major postoperative complications were pulmonary complications and nonpulmonary complications. The pulmonary complications included pulmonary infection, acute lung injury or acute respiratory distress syndrome and reintubation or invasive mechanical ventilation. Nonpulmonary complications included anastomotic fistula, incision infection, ICU stay and death before hospital discharge. Bronchoalveolar lavage was performed after induction of general anesthesia (baseline) and at the end of the surgical procedures. BALF was aspirated from the lung after instillation of 20 mL of sterile isotonic saline. Then, the recovered BALF was centrifuged at 700 g for 10 minutes at 4°C, and the supernatant was stored at -80°C. The cell pellets were resuspended in ice-cold sterile isotonic saline for staining and counting. Blood samples were obtained during TLV after induction of general anesthesia (baseline) and at the end of the surgical procedures. Five milliliters of arterial blood samples was centrifuged at 800 g for 5 minutes. The upper serum phase was separated and stored at -80°C. MT, IL-18 and IL-1β concentrations in the serum and BALF were determined using commercial ELISA kits (Cusabio, Wuhan, China). We performed the assays according to the manufacturer’s instructions. The limitations for MT, IL-18 and IL-1β were 0.1 pg/mL, 7.8 pg/mL and 2.2 pg/mL, respectively. Statistical Analysis According to previous studies, the cell numbers in the BALF increased by more than 30% after OLV [5], which required 12 patients per group with α=0.05 and β=0.02; thus, we aimed to enroll 88 patients to allow for dropouts. The sample size was calculated using PASS 11.0 software. Data are presented as the mean ± SD or number of patients (proportion, %). The independent-samples t-test or paired-samples t-test were used to analyze normally distributed data. Non-normally distributed data were analyzed by chi-square tests or Fisher’s exact test. All statistical analyses were performed with SPSS 19, and a P value of < 0.05 was considered significant. Results Baseline Parameters of Patients 88 patients were included and assessed. Four patients did not meet the criteria, and 84 were included in this study. However, two patients withdrew for technical reasons, and the other patient were excluded for higher Pplat. Finally, 81 patients completed the study (Fig. 1 ). The patient characteristics and preoperative details showed no significant differences between the two groups (Table 1 ). Table 1 Baseline parameters of patients Group A (n = 40) Group B (n = 41) P Male/Female (n) 36/4 35/6 0.529 Age (y) 63.25 ± 6.91 64.46 ± 6.95 0.433 BMI (kg/m 2 ) 23.93 ± 2.20 24.16 ± 1.89 0.614 Oxygenation index (mm Hg) 409.78 ± 21.91 406.11 ± 19.65 0.431 PaCO2 (mm Hg) 40.05 ± 3.26 40.29 ± 2.99 0.728 SpO2 (%) 98.63 ± 1.08 98.73 ± 1.12 0.663 FEV1(%) 86.58 ± 6.12 85.64 ± 6.31 0.500 FVC(%) 91.40 ± 9.31 88.65 ± 6.39 0.127 Operative time (min) 291.60 ± 35.41 293.46 ± 40.97 0.827 OLV time (min) 110.25 ± 24.17 118.15 ± 25.06 0.153 Data were presented as numbers or the mean ± SD. Group A: the patients chose volume controlled mechanical ventilation with a routine tidal volume (Vt = 10 mL/kg) as control; Group B: the patients chose lung protective ventilation with a low tidal volume (Vt = 5 mL/kg) and 5 cm H 2 O PEEP. BMI: body mass index; PaO 2 : arterial oxygen tension; FiO 2 : fraction of inspired oxygen; PaCO 2 : arterial carbon dioxide tension; FEV1: forced expiratory volume; FVC: forced vital capacity; OLV: one-lung ventilation; SpO 2 , oxygen saturation. Changes In Respiratory Parameters The respiratory and gas exchange variables are presented in Table 2 . The Ppeak, Pplat and ΔP were significantly decreased in the protective ventilation group. While the respiratory rate increased substantially compared with that in the control group. Additionally, the oxygenation index in the protective ventilation group was higher than that in the control group at 30 minutes after OLV (P = 0.006). Table 2 Respiratory variables and Oxygenation Index During TLV Before Surgery (At baseline) and During OLV (After 30 min) Group A (n = 40) Group B (n = 41) P Peak pressure (cm H 2 O) At baseline 14.85 ± 2.38 13.41 ± 1.53 0.002 a 30 min after OLV 26.63 ± 1.93 22.22 ± 2.12 < 10 − 3a Plateau pressure (cm H 2 O) At baseline 11.78 ± 2.19 10.49 ± 1.52 0.003 a 30 min after OLV 22.90 ± 2.13 19.00 ± 1.99 < 10 − 3a Driving pressure (cm H 2 O) At baseline 11.78 ± 2.19 5.49 ± 1.52 < 10 − 3a 30 min after OLV 22.90 ± 2.13 14.00 ± 1.99 < 10 − 3a Oxygenation index (mmHg) At baseline 406.42 ± 30.38 407.57 ± 26.72 0.857 30 min after OLV 314.70 ± 26.02 332.57 ± 30.52 0.006 a Respiratory rate (bpm) At baseline 10.408 ± 1.61 14.39 ± 1.24 < 10 − 3a 30 min after OLV 13.35 ± 1.08 17.54 ± 1.03 < 10 − 3a Data were presented as the mean and SD. Group A: the patients chose volume controlled mechanical ventilation with a routine tidal volume (Vt = 10 mL/kg) as control; Group B: the patients chose lung protective ventilation with a low tidal volume (Vt = 5 mL/kg) and 5 cm H 2 O PEEP. OLV: one-lung ventilation; TLV: two-lung ventilation. a Compared Group A with Group B, P < 0.05 Changes In The Number Of Cells In The Balf The cells in the BALF were counted after Wright-Giemsa staining. The number of total cells (in groups A and B, P = 0.000) and PMN cells (in groups A and B, P = 0.000) in the BALF were substantially increased after mechanical ventilation (Fig. 2 ). However, in the group treated with the lung-protective strategy, the total cells (P = 0.000) and PMN cells (P = 0.000) in the BALF were significantly reduced compared to the control group (Fig. 2 ). Changes in IL-1β and IL-18 Levels in the BALF and Serum Commercial ELISA kits were used to detect the levels of both IL-1β and IL-18 in the BALF and serum. The IL-1β and IL-18 levels in the BALF and serum showed an increasing trend after mechanical ventilation (Fig. 3 A, B, D and E). However, lung protective ventilation resulted in a significant decrease in the BALF and serum IL-1β and IL-18 concentrations compared to the control group (Fig. 3 A, B, D and E). Changes In Mt Levels In The Balf And Serum Endogenous MT levels in both the BALF and serum were also detected. In contrast to the IL-18 and IL-1β levels, the BALF and serum MT levels were significantly decreased in both groups after mechanical ventilation (Fig. 3 C, F). Additionally, lower BALF and serum MT concentrations were observed in the control group than in the lung protective ventilation group (Fig. 3 C and F). The Incidence Of Complications Pulmonary complications occurred in 2/41(4.88%) patients in the protective ventilation group and 8/40 (20%) patients in the control group (P = 0.04). 2 (4.88%) patient in the protective ventilation group developed a nonpulmonary complication compared with 4 (10%) patients in the control group (P = 0.382). The rate of major postoperative complications was 9.76% and 30% in the protective ventilation group and control group, respectively (P = 0.023). The incidence of major postoperative complications was lower in the lung protection group than in the control group (Table 3 ). Table 3 Outcomes analysis Group A (n = 40) Group B (n = 41) P Incidence of Complications (%) 12(30%) 4(9.76%) 0.023 a Pulmonary complications 8(20%) 2(4.88%) 0.040 a Pulmonary infection 4 1 0.160 ALI/ARDS 2 1 0.544 Reintubation 2 0 0.150 Nonpulmonary complications 4(10%) 2(4.88%) 0.382 Anastomotic fistula 1 1 0.986 Incision infection 1 1 0.986 ICU stay 2 0 0.150 Hospital death 0 0 1.0 Date were presented as numbers and percentage. ALI: acute lung injury; ARDS: acute respiratory distress syndrome. Group A: the patients chose volume controlled mechanical ventilation with a routine tidal volume (Vt = 10 mL/kg) as control; Group B: the patients chose lung protective ventilation with a low tidal volume (Vt = 5 mL/kg) and 5 cm H 2 O PEEP. a Compared Group A with Group B, P < 0.05 Discussion As shown in the present study, lung protective ventilation improved respiratory variables, including Ppeak, Pplat and ΔP. Lung protective ventilation not only inhibited PMN cell invasion but also suppressed IL-1β and IL-18 secretion. Lung protective ventilation resulted in a decrease in the inhibition of endogenous MT production compared to “conventional” ventilation. In addition, lung protective ventilation decreased the incidence of pulmonary complications and major postoperative complications. OLV is an established procedure performed during VATS. However, clinical studies have shown that the extended use of OLV is an independent risk factor for postoperative pulmonary dysfunction [ 17 ]. Excessive stretching or repeated opening of lung tissues is an important cause of VILI during OLV [ 18 ]. A lung-protective strategy using low Vt along with PEEP during OLV was confirmed to improve postoperative pulmonary dysfunction [ 6 ]. In our study, the lung-protective strategy notably decreased Ppeak and Pplat, indicating that the shear force was reduced by the lung-protective strategy. Meanwhile, we also observed a substantial decrease in ΔP with the lung-protective strategy, which suggested that the lung-protective strategy was associated with a reduced incidence of postoperative pulmonary complications [ 16 ]. Indeed, postoperative pulmonary complications occurred less frequently in the lung protective ventilation group in our study. Increased mechanical strain further activating the inflammatory response is a key event during the development of VILI [ 5 ]. The results from previous and recent studies have shown that IL-1β is a special proinflammatory cytokine that promotes VILI in animal models and patients [ 19 – 22 ]. Regulation and inhibition of IL-1β can finally achieve organ protection because blockade of the IL-1 receptor has been demonstrated to inhibit neutrophil sequestration and edema formation in VILI [ 23 ]. In our study, mechanical ventilation clearly increased the alveolar and serum concentration of IL-1β and the alveolar PMN cell counts in the BALF. However, lung protective ventilation blocked the elevated IL-1β level and PMN cell infiltration. Most interestingly, we observed a dramatic increase in both the alveolar and serum concentrations of IL-18 after OLV, while lung protective ventilation resulted in a profound reduction in IL-18 levels. IL-1β and IL-18 were confirmed to be products of NLRP3 inflammasome activation [ 24 ]. Furthermore, current studies have demonstrated that NLRP3 inflammasome activation plays a key role in the pathogenesis of VILI in a mouse model [ 25 , 26 ]. Therefore, lung protective ventilation may inhibit inflammatory responses by inhibiting the activation of the NLRP3 inflammasome. For the first time, we showed that mechanical ventilation may activate the NLRP3 inflammasome, and lung protective ventilation seems to inhibit the NLRP3 inflammasome activation in patients. In recent years, the anti-inflammatory effects of both exogenous and endogenous MT have been observed in many conditions [ 27 , 28 ]. Paula et al. demonstrated that the exogenous addition of MT protected against VILI through decreasing the levels of inflammatory cytokines in a mouse model [ 14 ]. Further research confirmed that exogenous replenishment of MT alleviated lipopolysaccharide-induced acute lung injury by inhibiting NLRP3 inflammasome activation [ 15 ]. However, researchers have not determined whether VILI affects the production of endogenous MT. Therefore, we hypothesized that endogenous MT may play a pivotal role in the pathogenesis of VILI. As expected, mechanical ventilation substantially reduced the levels of endogenous MT in patient serum and BALF. Surprisingly, pulmonary protective ventilation significantly inhibited the reduction of endogenous MT. Accordingly, our results suggested that endogenous MT may be involved in the pathogenesis of VILI, and pulmonary protective ventilation may attenuate VILI by restoring the level of endogenous MT in patients. As described above, lung protective ventilation not only improved respiratory parameters but also suppressed NLRP3 inflammasome-related inflammatory cytokine secretion and restored the level of endogenous MT: which are likely to be required to improve outcomes during esophageal surgery. Indeed, lung protective ventilation not only reduced the incidence of pulmonary complications but also decreased the rate of major postoperative complications in our study, consistent with the results reported by Marret [ 29 ]. This study has some limitations. First, the sizes of the samples were small, which may lead to bias. Second, based on our data, we were unable to conclusively determine the relationship between inflammasome-related inflammatory cytokines and endogenous MT. Therefore, the crosstalk between endogenous MT and the NLRP3 inflammasome in VILI requires further animal experiments. Conclusions In conclusion, pulmonary protective ventilation improved outcomes by decreasing the rate of pulmonary complications and major postoperative complications. These effects may be attributed to the ability of pulmonary protective ventilation to suppress NLRP3 inflammasome-related inflammatory cytokine secretion and restore the level of endogenous MT in patients undergoing VATS. Abbreviations OLV one-lung ventilation VILI ventilator-induced lung injury PEEP positive end-expiratory pressure IL interleukin TNF tumor necrosis factor BALF bronchoalveolar lavage fluid PMN polymorphonuclear NLRP3 Nucleotide-binding domain and leucine-rich repeat protein 3 MT melatonin FEV forced expiratory volume FVC forced vital capacity BMI body mass index TLV two-lung ventilation IBW ideal body weight ETCO2 end-tidal pressure of carbon dioxide Ppeak peak airway pressure Pplat plateau airway pressure ΔP driving pressure Declarations Ethics approval and consent to participate The study protocol had received prior approval by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (No. 20190385). In the study, all patients signed written informed consent. Consent for publication All authors have consented to publication of the manuscript. Availability of data and materials The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare no conflicts of interests. Funding This work was supported by grants from the National Nature Science Foundation of China (No. 81902003), Youth Research Foundation of the Anhui Medical University First Affiliated Hospital (Nos. 2018kj28 and 2019kj11), Doctoral Research Foundation of the First Affiliated Hospital of Anhui Medical University (No. 1326). Authors' Contributions LXW, JL and YTH collected the data, and drafted the manuscript, they contributed equally as co-first authors; YZ performed the statistical analysis; QYS and HYZ revised the manuscript critically for important intellectual content. All authors were responsible for the conception and design of the trial, and approved the final manuscript. Acknowledgments We acknowledge the support by Dr. Zhilai Yang. 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Supplementary Files CONSORT2010ChecklistMSWord.doc Cite Share Download PDF Status: Under Review Version 1 posted Review # 1 received at journal 17 May, 2021 Review # 2 received at journal 05 May, 2021 Reviewer # 2 agreed at journal 30 Apr, 2021 Reviewer # 1 agreed at journal 03 Feb, 2021 Reviewers invited by journal 13 Aug, 2020 Submission checks completed at journal 12 Aug, 2020 Editor invited by journal 12 Aug, 2020 Editor assigned by journal 12 Aug, 2020 First submitted to journal 01 Aug, 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. 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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-52115\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research article\",\"associatedPublications\":[],\"authors\":[{\"id\":1393431,\"identity\":\"511c4524-9c6c-4497-9238-6d19976e0f7a\",\"order_by\":0,\"name\":\"Lixia Wang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"First Affiliated Hospital of Anhui Medical University\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Lixia\",\"middleName\":\"\",\"lastName\":\"Wang\",\"suffix\":\"\"},{\"id\":1393432,\"identity\":\"699d78b4-3dfc-48de-88b6-3368ed14fa6e\",\"order_by\":1,\"name\":\"Jun Li\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"First Affiliated Hospital of Anhui Medical University\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Jun\",\"middleName\":\"\",\"lastName\":\"Li\",\"suffix\":\"\"},{\"id\":1393433,\"identity\":\"8c1e3ef0-a060-470a-9fad-86db896375fb\",\"order_by\":2,\"name\":\"Yuting Huang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Anhui Medical University\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yuting\",\"middleName\":\"\",\"lastName\":\"Huang\",\"suffix\":\"\"},{\"id\":1393434,\"identity\":\"36577a10-afbc-486c-9fef-564a45291aaf\",\"order_by\":3,\"name\":\"Yan Zhu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"First Affiliated Hospital of Anhui Medical University\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yan\",\"middleName\":\"\",\"lastName\":\"Zhu\",\"suffix\":\"\"},{\"id\":1393435,\"identity\":\"01b8dd06-cb61-4e6b-aaa8-0d0317129f76\",\"order_by\":4,\"name\":\"Qiying Shen\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"First Affiliated Hospital of Anhui Medical University\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Qiying\",\"middleName\":\"\",\"lastName\":\"Shen\",\"suffix\":\"\"},{\"id\":1393436,\"identity\":\"d5a982d9-89cb-40af-a27c-3d5bb044eecd\",\"order_by\":5,\"name\":\"Hongyun Zou\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"First Affiliated Hospital of Anhui Medical University\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Hongyun\",\"middleName\":\"\",\"lastName\":\"Zou\",\"suffix\":\"\"},{\"id\":1393437,\"identity\":\"605c74e6-45a8-431a-9c6d-45d15327c0d1\",\"order_by\":6,\"name\":\"Xuesheng Liu\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYBACPmYInQDEjA8YG8AcA7xa2JC0MBsQp4UBoYVNgjgt7Dxm0jwVdXn80u3XKn7u2JbYwN68TYKh5g4eh/EYG/OcOVwsOedM2c3eM7cTG3iOlUkwHHuGT4vhY962A4kbbuSk3eBtA2qRyDEDuvAwPi0Gh3n/1SXuB2op/AvSIv+GoBagLQ3MiRsk0o8xQ2zhIaSFrdhwzrHDiTNu5DBLy7bdNm7jSSu2SDiGWws//+FtEm9q6hL7Z6Q//Pi27bZsP/vhjTc+1ODWggR4INEBjqkEYjQwMLA/IE7dKBgFo2AUjDgAAJRhUs+LX658AAAAAElFTkSuQmCC\",\"orcid\":\"https://orcid.org/0000-0003-4324-282X\",\"institution\":\"First Affiliated Hospital of Anhui Medical University\",\"correspondingAuthor\":true,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Xuesheng\",\"middleName\":\"\",\"lastName\":\"Liu\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2020-08-01 10:29:22\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-52115/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-52115/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":1913224,\"identity\":\"ed9eff7e-c5db-428c-a857-52ac5467fa90\",\"added_by\":\"auto\",\"created_at\":\"2020-08-13 15:17:06\",\"extension\":\"jpg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":380067,\"visible\":true,\"origin\":\"\",\"legend\":\"Consort flow chart that outline patients assignment and treatment protocols. Group A: Volume controlled mechanical ventilation with a tidal volume of 10 mL/kg was used; Group B: lung protective ventilation with a low tidal volume (Vt=5 mL/kg IBW) and 5 cm H2O PEEP was chosen.\",\"description\":\"\",\"filename\":\"fig1.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-52115/v1/fig1.jpg\"},{\"id\":1913225,\"identity\":\"d3414920-7358-4cc0-a910-f26176d3e8d4\",\"added_by\":\"auto\",\"created_at\":\"2020-08-13 15:17:06\",\"extension\":\"jpg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":270570,\"visible\":true,\"origin\":\"\",\"legend\":\"Effect of lung protective ventilation on polymorphonuclear (PMN) cells in BALF. (A) Representative Wright-Giemsa stained smear of BALF from different groups (magnification ×20). Data shown represent changes in the total number of cells (B), PMN cells (C) in the BALF. Data are expressed as the mean ± SD of 30 patients per group.\",\"description\":\"\",\"filename\":\"fig2.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-52115/v1/fig2.jpg\"},{\"id\":1913226,\"identity\":\"09934cce-fdfc-478d-ab70-49eb14389e12\",\"added_by\":\"auto\",\"created_at\":\"2020-08-13 15:17:06\",\"extension\":\"jpg\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":243845,\"visible\":true,\"origin\":\"\",\"legend\":\"Effect of lung protective ventilation on IL-1β, IL-18 and endogenous melatonin production in BALF and serum. (A-C) Productions of IL-1β, IL-18 and endogenous melatonin in the BALF. (D-F) Productions of IL-1β, IL-18 and endogenous melatonin in the serum. Data are expressed as the mean ± SD of 30 patients per group.\",\"description\":\"\",\"filename\":\"fig3.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-52115/v1/fig3.jpg\"},{\"id\":13574686,\"identity\":\"3c5192bf-dca0-4611-bd8d-ad3cdcc92c88\",\"added_by\":\"auto\",\"created_at\":\"2021-09-17 04:00:00\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":637423,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-52115/v1/ff710c42-c9f2-42d1-8aa7-8975903cd6b8.pdf\"},{\"id\":1913228,\"identity\":\"26c30243-09c2-43af-b4d4-0eb04f06f751\",\"added_by\":\"auto\",\"created_at\":\"2020-08-13 15:17:07\",\"extension\":\"doc\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":226816,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"CONSORT2010ChecklistMSWord.doc\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-52115/v1/CONSORT2010ChecklistMSWord.doc\"}],\"financialInterests\":\"\",\"formattedTitle\":\"The Effects of Protective Ventilation on the Production of Endogenous Melatonin and Prognosis in Patients Undergoing Esophageal Cancer Surgery: A Prospective Randomized Double-Blind Controlled Study\",\"fulltext\":[{\"header\":\"Background\",\"content\":\" \\u003cp\\u003eOne-lung ventilation (OLV) is required for esophageal cancer and can contribute to the surgical field [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. However, inappropriate ventilation modes may cause or augment acute lung injury, which is known as ventilator-induced lung injury (VILI) [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. Lung protective ventilation [low tidal volume\\u0026thinsp;+\\u0026thinsp;positive end-expiratory pressure (PEEP)] was shown to achieve good clinical effects and protect against VILI [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. Furthermore, clinical studies have demonstrated that lung protective ventilation induced an immune response with lower concentrations of inflammatory mediators than that of \\u0026ldquo;conventional\\u0026rdquo; ventilation [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]. Therefore, further studies of the effect of lung protective ventilation on the pulmonary immune response are essential to prevent VILI.\\u003c/p\\u003e \\u003cp\\u003eIncreasing studies have shown that OLV may lead to proinflammatory cytokine release and inflammatory signaling pathway activation [\\u003cspan additionalcitationids=\\\"CR6 CR7\\\" citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]. Overdistension in ventilated lungs followed by compression of alveolar vessels initiates a robust release of proinflammatory cytokines, such as interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-a, in bronchoalveolar lavage fluid (BALF) [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. These proinflammatory cytokines are important chemotactic factors for polymorphonuclear (PMN) cells [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]. Excessive PMN cell aggregation will amplify the inflammatory cascade. Furthermore, a recent study showed that in mouse alveolar macrophages, Nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome activation contributes to the development of VILI [\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eMelatonin (N-acetyl-5-methoxytryptamine, MT), which is mainly secreted in the pineal gland, has well-documented anti-inflammatory and immunomodulatory functions [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]. Early preliminary studies have shown that exogenous MT ameliorates VILI by increasing the anti-inflammatory response [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. Recently, Zhang et al. demonstrated that exogenous MT inhibited NLRP3 inflammasome activation in mice with acute lung injury [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]. However, researchers have not determined whether lung protective ventilation affects NLRP3 inflammasome-related inflammatory cytokine and endogenous melatonin production in patients.\\u003c/p\\u003e \\u003cp\\u003eOur study aimed to investigate the effects of lung protective ventilation on NLRP3 inflammasome-related inflammatory cytokine and endogenous MT secretion in patients undergoing video-assisted thoracoscopic esophagectomy (VATS). In addition, the effect of lung protective ventilation on postoperative complications was also investigated.\\u003c/p\\u003e \"},{\"header\":\"Materials And Methods\",\"content\":\"\\u003ch2\\u003eStudy Design\\u003c/h2\\u003e\\n\\u003cp\\u003ePatients scheduled for elective VATS at the First Affiliated Hospital of Anhui Medical University (Anhui, China) were included in the study. The study protocol had received prior approval from the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (No. 20190385), and this trial was registered in the Chinese Clinical Trial Registry (No. ChiCTR1900026190). Before participation in the study, all patients provided informed consent.\\u003c/p\\u003e\\n\\u003ch2\\u003eStudy Population\\u003c/h2\\u003e\\n\\u003cp\\u003ePatients with esophageal cancer who were treated at our hospital were considered for enrollment. The inclusion criteria were as follows: American Society of Anesthesiologists (ASA) physical status I - Ⅲ, requirement for OLV during operation, and aged 45\\u0026ndash;77 years. Exclusion criteria were preexisting hypoxemia, diagnosed major obstructive or restrictive pulmonary disease [preoperative forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) \\u0026lt;70% of the predicted value], pulmonary infection before surgery, body mass index (BMI) of less than 20 or more than 35, and use of immune modulators.\\u003c/p\\u003e\\n\\u003ch2\\u003eRandomization and Blinding\\u003c/h2\\u003e\\n\\u003cp\\u003eThe randomized numbers were generated by a research coordinator using block sizes on a 1:1 ratio. This ensured that each group had an equal number of subjects. Then, the research coordinator sealed the numbers in opaque envelopes. Before mechanical ventilation, the anesthesia assistant opened the envelopes, set the breathing parameters and covered the breathing parameters using opaque paper. The anesthesia assistant did not participate in the next study. One anesthesiologist collected the specimens, and another anesthesiologist recorded the breathing parameters. Both physicians were blinded to the allocation.\\u003c/p\\u003e\\n\\u003ch2\\u003eStudy Protocol\\u003c/h2\\u003e\\n\\u003cp\\u003eStandard monitoring devices were applied after admission to the operating room. Before induction of anesthesia, an artery catheter was inserted into the left radial artery. Anesthesia induction was performed with 2.0-2.5 mg/kg propofol, 0.02-0.06 mg/kg midazolam, 0.4-0.6 \\u0026micro;g/kg sufentanil and 0.6-0.9 mg/kg rocuronium. 3 min after assisted breathing, a double-lumen endotracheal tube (Broncho-Cath\\u003csup\\u003e\\u0026reg;\\u003c/sup\\u003e 35 F or 37 F; Covidien, Ireland) was inserted into the left main bronchus. Anesthesia was maintained with 50\\u0026ndash;100 \\u0026micro;g/kg/min of propofol, 0.1\\u0026ndash;1 \\u0026micro;g/kg/min of remifentanil and 5.0\\u0026ndash;10.0 \\u0026micro;g/kg/min of rocuronium to maintain the proper depth of anesthesia (BIS 40\\u0026ndash;60). A forced-air warming system (3M Company, Shanghai, China) was used to keep the patients warm.\\u003c/p\\u003e\\n\\u003cp\\u003eAfter intubation, the patients were randomly divided into 2 groups. In the control group (group A), patients received volume controlled mechanical ventilation with a tidal volume of 10 mL/kg of ideal body weight (IBW). In the lung protective ventilation group (group B), lung protective ventilation with a low tidal volume (Vt=5 mL/kg IBW) and 5 cm H\\u003csub\\u003e2\\u003c/sub\\u003eO PEEP was chosen. After 15 minutes, all patients were turned to the left lateral position and OLV was initiated. During OLV, the ventilation mode was not changed except the plateau airway pressure (Pplat) exceeded 30 cmH\\u003csub\\u003e2\\u003c/sub\\u003eO. If the Pplat exceeded 30 cmH\\u003csub\\u003e2\\u003c/sub\\u003eO, the tidal volume was decreased and this patient discontinued the experiment. With both two-lung ventilation (TLV) and OLV, mechanical ventilation was performed with an inspiratory to expiratory ratio of 1:2, and an appropriate respiratory rate to maintain an end-tidal CO\\u003csub\\u003e2\\u003c/sub\\u003e (ETCO\\u003csub\\u003e2\\u003c/sub\\u003e) below 45 mmHg. All surgeries were always performed at 8:30 in the morning.\\u003c/p\\u003e\\n\\u003ch2\\u003eObservational Indexes\\u003c/h2\\u003e\\n\\u003cp\\u003ePeak airway pressure (Ppeak), Pplat, respiratory rate and blood gas analyses were evaluated at two stages: during TLV before surgery and 30 minutes after OLV. Furthermore, the driving pressure (\\u0026Delta;P) was recorded. \\u0026Delta;P was defined and calculated as follows: \\u0026Delta;P=Pplat\\u0026ndash;PEEP [16].\\u003c/p\\u003e\\n\\u003cp\\u003eThe major postoperative complications were pulmonary complications and nonpulmonary complications. The pulmonary complications included pulmonary infection, acute lung injury or acute respiratory distress syndrome and reintubation or invasive mechanical ventilation. Nonpulmonary complications included anastomotic fistula, incision infection, ICU stay and death before hospital discharge.\\u003c/p\\u003e\\n\\u003cp\\u003eBronchoalveolar lavage was performed after induction of general anesthesia (baseline) and at the end of the surgical procedures. BALF was aspirated from the lung after instillation of 20 mL of sterile isotonic saline. Then, the recovered BALF was centrifuged at 700 g for 10 minutes at 4\\u0026deg;C, and the supernatant was stored at -80\\u0026deg;C. The cell pellets were resuspended in ice-cold sterile isotonic saline for staining and counting.\\u003c/p\\u003e\\n\\u003cp\\u003eBlood samples were obtained during TLV after induction of general anesthesia (baseline) and at the end of the surgical procedures. Five milliliters of arterial blood samples was centrifuged at 800 g for 5 minutes. The upper serum phase was separated and stored at -80\\u0026deg;C.\\u003c/p\\u003e\\n\\u003cp\\u003eMT, IL-18 and IL-1\\u0026beta; concentrations in the serum and BALF were determined using commercial ELISA kits (Cusabio, Wuhan, China). We performed the assays according to the manufacturer\\u0026rsquo;s instructions. The limitations for MT, IL-18 and IL-1\\u0026beta; were 0.1 pg/mL, 7.8 pg/mL and 2.2 pg/mL, respectively.\\u003c/p\\u003e\\n\\u003ch2\\u003eStatistical Analysis\\u003c/h2\\u003e\\n\\u003cp\\u003eAccording to previous studies, the cell numbers in the BALF increased by more than 30% after OLV [5], which required 12 patients per group with \\u0026alpha;=0.05 and \\u0026beta;=0.02; thus, we aimed to enroll 88 patients to allow for dropouts. The sample size was calculated using PASS 11.0 software.\\u003c/p\\u003e\\n\\u003cp\\u003eData are presented as the mean \\u0026plusmn; SD or number of patients (proportion, %). The independent-samples t-test or paired-samples t-test were used to analyze normally distributed data. Non-normally distributed data were analyzed by chi-square tests or Fisher\\u0026rsquo;s exact test. All statistical analyses were performed with SPSS 19, and a P value of \\u0026lt; 0.05 was considered significant.\\u003c/p\\u003e\"},{\"header\":\"Results\",\"content\":\" \\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eBaseline Parameters of Patients\\u003c/h2\\u003e \\u003cp\\u003e88 patients were included and assessed. Four patients did not meet the criteria, and 84 were included in this study. However, two patients withdrew for technical reasons, and the other patient were excluded for higher Pplat. Finally, 81 patients completed the study (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). The patient characteristics and preoperative details showed no significant differences between the two groups (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eBaseline parameters of patients\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"4\\\"\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eGroup A (n\\u0026thinsp;=\\u0026thinsp;40)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eGroup B (n\\u0026thinsp;=\\u0026thinsp;41)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eP\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eMale/Female (n)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e36/4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e35/6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.529\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAge (y)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e63.25\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;6.91\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e64.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;6.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.433\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBMI (kg/m\\u003csup\\u003e2\\u003c/sup\\u003e)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e23.93\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.20\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e24.16\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.89\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.614\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eOxygenation index (mm Hg)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e409.78\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;21.91\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e406.11\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;19.65\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.431\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePaCO2 (mm Hg)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e40.05\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;3.26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e40.29\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.99\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.728\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSpO2 (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e98.63\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.08\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e98.73\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.663\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFEV1(%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e86.58\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;6.12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e85.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;6.31\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.500\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFVC(%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e91.40\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;9.31\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e88.65\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;6.39\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.127\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eOperative time (min)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e291.60\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;35.41\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e293.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;40.97\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.827\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eOLV time (min)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e110.25\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;24.17\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e118.15\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;25.06\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.153\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"4\\\"\\u003eData were presented as numbers or the mean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD. Group A: the patients chose volume controlled mechanical ventilation with a routine tidal volume (Vt\\u0026thinsp;=\\u0026thinsp;10\\u0026nbsp;mL/kg) as control; Group B: the patients chose lung protective ventilation with a low tidal volume (Vt\\u0026thinsp;=\\u0026thinsp;5\\u0026nbsp;mL/kg) and 5\\u0026nbsp;cm H\\u003csub\\u003e2\\u003c/sub\\u003eO PEEP. BMI: body mass index; PaO\\u003csub\\u003e2\\u003c/sub\\u003e: arterial oxygen tension; FiO\\u003csub\\u003e2\\u003c/sub\\u003e: fraction of inspired oxygen; PaCO\\u003csub\\u003e2\\u003c/sub\\u003e: arterial carbon dioxide tension; FEV1: forced expiratory volume; FVC: forced vital capacity; OLV: one-lung ventilation; SpO\\u003csub\\u003e2\\u003c/sub\\u003e, oxygen saturation.\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\n\\u003ch2\\u003eChanges In Respiratory Parameters\\u003c/h2\\u003e\\n \\u003cp\\u003eThe respiratory and gas exchange variables are presented in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e. The Ppeak, Pplat and ΔP were significantly decreased in the protective ventilation group. While the respiratory rate increased substantially compared with that in the control group. Additionally, the oxygenation index in the protective ventilation group was higher than that in the control group at 30 minutes after OLV (P\\u0026thinsp;=\\u0026thinsp;0.006).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eRespiratory variables and Oxygenation Index During TLV Before Surgery (At baseline) and During OLV (After 30\\u0026nbsp;min)\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"6\\\"\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003eGroup A (n\\u0026thinsp;=\\u0026thinsp;40)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003eGroup B (n\\u0026thinsp;=\\u0026thinsp;41)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eP\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003ePeak pressure (cm H\\u003c/b\\u003e\\u003csub\\u003e\\u003cb\\u003e2\\u003c/b\\u003e\\u003c/sub\\u003e\\u003cb\\u003eO)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAt baseline\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003e14.85\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.38\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e13.41\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.53\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.002\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e30\\u0026nbsp;min after OLV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003e26.63\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.93\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e22.22\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;10\\u003csup\\u003e\\u0026minus;\\u0026thinsp;3a\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003ePlateau pressure (cm H\\u003c/b\\u003e\\u003csub\\u003e\\u003cb\\u003e2\\u003c/b\\u003e\\u003c/sub\\u003e\\u003cb\\u003eO)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAt baseline\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003e11.78\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.19\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e10.49\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.52\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.003\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e30\\u0026nbsp;min after OLV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003e22.90\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e19.00\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.99\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;10\\u003csup\\u003e\\u0026minus;\\u0026thinsp;3a\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eDriving pressure (cm H\\u003c/b\\u003e\\u003csub\\u003e\\u003cb\\u003e2\\u003c/b\\u003e\\u003c/sub\\u003e\\u003cb\\u003eO)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAt baseline\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003e11.78\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.19\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e5.49\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.52\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;10\\u003csup\\u003e\\u0026minus;\\u0026thinsp;3a\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e30\\u0026nbsp;min after OLV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003e22.90\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e14.00\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.99\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;10\\u003csup\\u003e\\u0026minus;\\u0026thinsp;3a\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eOxygenation index (mmHg)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c4\\\" namest=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAt baseline\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003e406.42\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;30.38\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e407.57\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;26.72\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.857\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e30\\u0026nbsp;min after OLV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003e314.70\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;26.02\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e332.57\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;30.52\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.006\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eRespiratory rate (bpm)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAt baseline\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003e10.408\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.61\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e14.39\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.24\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;10\\u003csup\\u003e\\u0026minus;\\u0026thinsp;3a\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e30\\u0026nbsp;min after OLV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003e13.35\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.08\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e17.54\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.03\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;10\\u003csup\\u003e\\u0026minus;\\u0026thinsp;3a\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"6\\\"\\u003eData were presented as the mean and SD. Group A: the patients chose volume controlled mechanical ventilation with a routine tidal volume (Vt\\u0026thinsp;=\\u0026thinsp;10\\u0026nbsp;mL/kg) as control; Group B: the patients chose lung protective ventilation with a low tidal volume (Vt\\u0026thinsp;=\\u0026thinsp;5\\u0026nbsp;mL/kg) and 5\\u0026nbsp;cm H\\u003csub\\u003e2\\u003c/sub\\u003eO PEEP. OLV: one-lung ventilation; TLV: two-lung ventilation. a Compared Group A with Group B, P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\n\\u003ch2\\u003eChanges In The Number Of Cells In The Balf\\u003c/h2\\u003e\\n \\u003cp\\u003eThe cells in the BALF were counted after Wright-Giemsa staining. The number of total cells (in groups A and B, P\\u0026thinsp;=\\u0026thinsp;0.000) and PMN cells (in groups A and B, P\\u0026thinsp;=\\u0026thinsp;0.000) in the BALF were substantially increased after mechanical ventilation (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). However, in the group treated with the lung-protective strategy, the total cells (P\\u0026thinsp;=\\u0026thinsp;0.000) and PMN cells (P\\u0026thinsp;=\\u0026thinsp;0.000) in the BALF were significantly reduced compared to the control group (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eChanges in IL-1β and IL-18 Levels in the BALF and Serum\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003eCommercial ELISA kits were used to detect the levels of both IL-1β and IL-18 in the BALF and serum. The IL-1β and IL-18 levels in the BALF and serum showed an increasing trend after mechanical ventilation (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003eA, B, D and E). However, lung protective ventilation resulted in a significant decrease in the BALF and serum IL-1β and IL-18 concentrations compared to the control group (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003eA, B, D and E).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\n\\u003ch2\\u003eChanges In Mt Levels In The Balf And Serum\\u003c/h2\\u003e\\n \\u003cp\\u003eEndogenous MT levels in both the BALF and serum were also detected. In contrast to the IL-18 and IL-1β levels, the BALF and serum MT levels were significantly decreased in both groups after mechanical ventilation (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003eC, F). Additionally, lower BALF and serum MT concentrations were observed in the control group than in the lung protective ventilation group (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003eC and F).\\u003c/p\\u003e \\n\\u003ch2\\u003eThe Incidence Of Complications\\u003c/h2\\u003e\\n \\u003cp\\u003ePulmonary complications occurred in 2/41(4.88%) patients in the protective ventilation group and 8/40 (20%) patients in the control group (P\\u0026thinsp;=\\u0026thinsp;0.04). 2 (4.88%) patient in the protective ventilation group developed a nonpulmonary complication compared with 4 (10%) patients in the control group (P\\u0026thinsp;=\\u0026thinsp;0.382). The rate of major postoperative complications was 9.76% and 30% in the protective ventilation group and control group, respectively (P\\u0026thinsp;=\\u0026thinsp;0.023). The incidence of major postoperative complications was lower in the lung protection group than in the control group (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eOutcomes analysis\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"4\\\"\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eGroup A (n\\u0026thinsp;=\\u0026thinsp;40)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eGroup B (n\\u0026thinsp;=\\u0026thinsp;41)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eP\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eIncidence of Complications (%)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e12(30%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e4(9.76%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.023\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003ePulmonary complications\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e8(20%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2(4.88%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.040\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePulmonary infection\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.160\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eALI/ARDS\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.544\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eReintubation\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.150\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eNonpulmonary complications\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e4(10%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2(4.88%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.382\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAnastomotic fistula\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.986\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIncision infection\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.986\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eICU stay\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.150\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHospital death\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e1.0\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"4\\\"\\u003eDate were presented as numbers and percentage. ALI: acute lung injury; ARDS: acute respiratory distress syndrome. Group A: the patients chose volume controlled mechanical ventilation with a routine tidal volume (Vt\\u0026thinsp;=\\u0026thinsp;10\\u0026nbsp;mL/kg) as control; Group B: the patients chose lung protective ventilation with a low tidal volume (Vt\\u0026thinsp;=\\u0026thinsp;5\\u0026nbsp;mL/kg) and 5\\u0026nbsp;cm H\\u003csub\\u003e2\\u003c/sub\\u003eO PEEP. a Compared Group A with Group B, P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \"},{\"header\":\"Discussion\",\"content\":\" \\u003cp\\u003eAs shown in the present study, lung protective ventilation improved respiratory variables, including Ppeak, Pplat and ΔP. Lung protective ventilation not only inhibited PMN cell invasion but also suppressed IL-1β and IL-18 secretion. Lung protective ventilation resulted in a decrease in the inhibition of endogenous MT production compared to \\u0026ldquo;conventional\\u0026rdquo; ventilation. In addition, lung protective ventilation decreased the incidence of pulmonary complications and major postoperative complications.\\u003c/p\\u003e \\u003cp\\u003eOLV is an established procedure performed during VATS. However, clinical studies have shown that the extended use of OLV is an independent risk factor for postoperative pulmonary dysfunction [\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e]. Excessive stretching or repeated opening of lung tissues is an important cause of VILI during OLV [\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. A lung-protective strategy using low Vt along with PEEP during OLV was confirmed to improve postoperative pulmonary dysfunction [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. In our study, the lung-protective strategy notably decreased Ppeak and Pplat, indicating that the shear force was reduced by the lung-protective strategy. Meanwhile, we also observed a substantial decrease in ΔP with the lung-protective strategy, which suggested that the lung-protective strategy was associated with a reduced incidence of postoperative pulmonary complications [\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]. Indeed, postoperative pulmonary complications occurred less frequently in the lung protective ventilation group in our study.\\u003c/p\\u003e \\u003cp\\u003eIncreased mechanical strain further activating the inflammatory response is a key event during the development of VILI [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]. The results from previous and recent studies have shown that IL-1β is a special proinflammatory cytokine that promotes VILI in animal models and patients [\\u003cspan additionalcitationids=\\\"CR20 CR21\\\" citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e]. Regulation and inhibition of IL-1β can finally achieve organ protection because blockade of the IL-1 receptor has been demonstrated to inhibit neutrophil sequestration and edema formation in VILI [\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]. In our study, mechanical ventilation clearly increased the alveolar and serum concentration of IL-1β and the alveolar PMN cell counts in the BALF. However, lung protective ventilation blocked the elevated IL-1β level and PMN cell infiltration. Most interestingly, we observed a dramatic increase in both the alveolar and serum concentrations of IL-18 after OLV, while lung protective ventilation resulted in a profound reduction in IL-18 levels. IL-1β and IL-18 were confirmed to be products of NLRP3 inflammasome activation [\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]. Furthermore, current studies have demonstrated that NLRP3 inflammasome activation plays a key role in the pathogenesis of VILI in a mouse model [\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e]. Therefore, lung protective ventilation may inhibit inflammatory responses by inhibiting the activation of the NLRP3 inflammasome. For the first time, we showed that mechanical ventilation may activate the NLRP3 inflammasome, and lung protective ventilation seems to inhibit the NLRP3 inflammasome activation in patients.\\u003c/p\\u003e \\u003cp\\u003eIn recent years, the anti-inflammatory effects of both exogenous and endogenous MT have been observed in many conditions [\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e]. Paula et al. demonstrated that the exogenous addition of MT protected against VILI through decreasing the levels of inflammatory cytokines in a mouse model [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. Further research confirmed that exogenous replenishment of MT alleviated lipopolysaccharide-induced acute lung injury by inhibiting NLRP3 inflammasome activation [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]. However, researchers have not determined whether VILI affects the production of endogenous MT. Therefore, we hypothesized that endogenous MT may play a pivotal role in the pathogenesis of VILI. As expected, mechanical ventilation substantially reduced the levels of endogenous MT in patient serum and BALF. Surprisingly, pulmonary protective ventilation significantly inhibited the reduction of endogenous MT. Accordingly, our results suggested that endogenous MT may be involved in the pathogenesis of VILI, and pulmonary protective ventilation may attenuate VILI by restoring the level of endogenous MT in patients.\\u003c/p\\u003e \\u003cp\\u003eAs described above, lung protective ventilation not only improved respiratory parameters but also suppressed NLRP3 inflammasome-related inflammatory cytokine secretion and restored the level of endogenous MT: which are likely to be required to improve outcomes during esophageal surgery. Indeed, lung protective ventilation not only reduced the incidence of pulmonary complications but also decreased the rate of major postoperative complications in our study, consistent with the results reported by Marret [\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eThis study has some limitations. First, the sizes of the samples were small, which may lead to bias. Second, based on our data, we were unable to conclusively determine the relationship between inflammasome-related inflammatory cytokines and endogenous MT. Therefore, the crosstalk between endogenous MT and the NLRP3 inflammasome in VILI requires further animal experiments.\\u003c/p\\u003e \"},{\"header\":\"Conclusions\",\"content\":\" \\u003cp\\u003eIn conclusion, pulmonary protective ventilation improved outcomes by decreasing the rate of pulmonary complications and major postoperative complications. These effects may be attributed to the ability of pulmonary protective ventilation to suppress NLRP3 inflammasome-related inflammatory cytokine secretion and restore the level of endogenous MT in patients undergoing VATS.\\u003c/p\\u003e \"},{\"header\":\"Abbreviations\",\"content\":\" \\u003cdiv class=\\\"DefinitionList\\\"\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eOLV\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eone-lung ventilation\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eVILI\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eventilator-induced lung injury\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003ePEEP\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003epositive end-expiratory pressure\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eIL\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003einterleukin\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eTNF\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003etumor necrosis factor\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eBALF\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003ebronchoalveolar lavage fluid\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003ePMN\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003epolymorphonuclear\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eNLRP3\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eNucleotide-binding domain and leucine-rich repeat protein 3\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eMT\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003emelatonin\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eFEV\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eforced expiratory volume\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eFVC\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eforced vital capacity\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eBMI\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003ebody mass index\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eTLV\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003etwo-lung ventilation\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eIBW\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eideal body weight\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eETCO2\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eend-tidal pressure of carbon dioxide\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003ePpeak\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003epeak airway pressure\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003ePplat\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eplateau airway pressure\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eΔP\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003edriving pressure\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \"},{\"header\":\"Declarations\",\"content\":\"\\u003ch2\\u003eEthics approval and consent to participate\\u003c/h2\\u003e\\n\\u003cp\\u003eThe study protocol had received prior approval by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (No. 20190385). In the study, all patients signed written informed consent.\\u003c/p\\u003e\\n\\u003ch2\\u003eConsent for publication\\u003c/h2\\u003e\\n\\u003cp\\u003eAll authors have consented to publication of the manuscript.\\u003c/p\\u003e\\n\\u003ch2\\u003eAvailability of data and materials\\u003c/h2\\u003e\\n\\u003cp\\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.\\u003c/p\\u003e\\n\\u003ch2\\u003eCompeting interests\\u003c/h2\\u003e\\n\\u003cp\\u003eThe authors declare no conflicts of interests.\\u003c/p\\u003e\\n\\u003ch2\\u003eFunding\\u003c/h2\\u003e\\n\\u003cp\\u003eThis work was supported by grants from the National Nature Science Foundation of China (No. 81902003), Youth Research Foundation of the Anhui Medical University First Affiliated Hospital (Nos. 2018kj28 and 2019kj11), Doctoral Research Foundation of the First Affiliated Hospital of Anhui Medical University (No. 1326).\\u003c/p\\u003e\\n\\u003ch2\\u003eAuthors' Contributions\\u003c/h2\\u003e\\n\\u003cp\\u003eLXW, JL and YTH collected the data, and drafted the manuscript, they contributed equally as co-first authors; YZ performed the statistical analysis; QYS and HYZ revised the manuscript\\u0026nbsp; critically for important intellectual content. All authors were responsible for the conception and design of the trial, and approved the final manuscript.\\u003c/p\\u003e\\n\\u003ch2\\u003eAcknowledgments\\u003c/h2\\u003e\\n\\u003cp\\u003eWe acknowledge the support by Dr. Zhilai Yang. We are also thankful to the patients and their families who consented to participate in our trial.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e \\u003cspan\\u003eBlank RS, Colquhoun DA, Durieux ME, et al. Management of One-lung Ventilation: Impact of Tidal Volume on Complications after Thoracic Surgery. Anesthesiology. 2016;124(6):1286\\u0026ndash;95.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eChoi YS, Shim JK, Na S, et al. Pressure-controlled versus volume-controlled ventilation during one-lung ventilation in the prone position for robot-assisted esophagectomy. Surgical endoscopy. 2009;23(10):2286\\u0026ndash;91.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eHemmes SN, Serpa Neto A, Schultz MJ. Intraoperative ventilatory strategies to prevent postoperative pulmonary complications: a meta-analysis. Curr Opin Anaesthesiol. 2013;26(2):126\\u0026ndash;33.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eFernandez-Perez ER, Keegan MT, Brown DR, et al. Intraoperative tidal volume as a risk factor for respiratory failure after pneumonectomy. Anesthesiology. 2006;105(1):14\\u0026ndash;8.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eSchilling T, Kozian A, Huth C, et al. The pulmonary immune effects of mechanical ventilation in patients undergoing thoracic surgery. Anesthesia analgesia. 2005;101(4):957\\u0026ndash;65. table of contents.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eSenturk M, Slinger P, Cohen E. Intraoperative mechanical ventilation strategies for one-lung ventilation. Best practice research Clinical anaesthesiology. 2015;29(3):357\\u0026ndash;69.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eKotani N, Lin CY, Wang JS, et al. Loss of alveolar macrophages during anesthesia and operation in humans. Anesthesia analgesia. 1995;81(6):1255\\u0026ndash;62.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eKotani N, Hashimoto H, Sessler DI, et al. Intraoperative modulation of alveolar macrophage function during isoflurane and propofol anesthesia. Anesthesiology. 1998;89(5):1125\\u0026ndash;32.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eLohser J, Slinger P, Lung Injury After One-Lung Ventilation. A Review of the Pathophysiologic Mechanisms Affecting the Ventilated and the Collapsed Lung. Anesthesia analgesia. 2015;121(2):302\\u0026ndash;18.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eDreyfuss D, Ricard JD, Saumon G. On the physiologic and clinical relevance of lung-borne cytokines during ventilator-induced lung injury. Am J Respir Crit Care Med. 2003;167(11):1467\\u0026ndash;71.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eWu J, Yan Z, Schwartz DE, \\u003cem\\u003eet al.\\u003c/em\\u003e Activation of NLRP3 inflammasome in alveolar macrophages contributes to mechanical stretch-induced lung inflammation and injury. Journal of immunology (Baltimore, Md: 1950). 2013;190(7):3590\\u0026ndash;3599.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eLiu YJ, Meng FT, Wang LL, et al. Apolipoprotein E influences melatonin biosynthesis by regulating NAT and MAOA expression in C6 cells. Journal of pineal research. 2012;52(4):397\\u0026ndash;402.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eCalvo JR, Gonzalez-Yanes C, Maldonado MD. The role of melatonin in the cells of the innate immunity: a review. Journal of pineal research. 2013;55(2):103\\u0026ndash;20.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003ePedreira PR, Garcia-Prieto E, Parra D, et al. Effects of melatonin in an experimental model of ventilator-induced lung injury. American journal of physiology Lung cellular molecular physiology. 2008;295(5):L820\\u0026ndash;7.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eZhang Y, Li X, Grailer JJ, et al. Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome. Journal of pineal research. 2016;60(4):405\\u0026ndash;14.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eNeto AS, Hemmes SN, Barbas CS, et al. Association between driving pressure and development of postoperative pulmonary complications in patients undergoing mechanical ventilation for general anaesthesia: a meta-analysis of individual patient data. The Lancet Respiratory medicine. 2016;4(4):272\\u0026ndash;80.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eDella Rocca G, Coccia C. Acute lung injury in thoracic surgery. Curr Opin Anaesthesiol. 2013;26(1):40\\u0026ndash;6.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eKim KN, Kim DW, Jeong MA, et al. Comparison of pressure-controlled ventilation with volume-controlled ventilation during one-lung ventilation: a systematic review and meta-analysis. BMC anesthesiology. 2016;16(1):72.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eBelperio JA, Keane MP, Lynch JP 3. The role of cytokines during the pathogenesis of ventilator-associated and ventilator-induced lung injury. Semin Respir Crit Care Med. 2006;27(4):350\\u0026ndash;64. rd, et al.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eLionetti V, Recchia FA, Ranieri VM. Overview of ventilator-induced lung injury mechanisms. Curr Opin Crit Care. 2005;11(1):82\\u0026ndash;6.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eWagner J, Strosing KM, Spassov SG, et al. Sevoflurane posttreatment prevents oxidative and inflammatory injury in ventilator-induced lung injury. PloS one. 2018;13(2):e0192896.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eConway Morris A, Kefala K, Wilkinson TS, et al. Diagnostic importance of pulmonary interleukin-1beta and interleukin-8 in ventilator-associated pneumonia. Thorax. 2010;65(3):201\\u0026ndash;7.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eFrank JA, Pittet JF, Wray C, et al. Protection from experimental ventilator-induced acute lung injury by IL-1 receptor blockade. Thorax. 2008;63(2):147\\u0026ndash;53.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eBryant C, Fitzgerald KA. Molecular mechanisms involved in inflammasome activation. Trends in cell biology. 2009;19(9):455\\u0026ndash;64.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eLiu H, Gu C, Liu M, et al. Ventilator-induced lung injury is alleviated by inhibiting NLRP3 inflammasome activation. Molecular immunology. 2019;111:1\\u0026ndash;10.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eAn X, Sun X, Yang X, et al Oxidative stress promotes ventilator-induced lung injury through activating NLRP3 inflammasome and TRPM2 channel. Artificial cells, nanomedicine, and biotechnology. 2019;47(1):3448\\u0026ndash;3455.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eMauriz JL, Collado PS, Veneroso C, et al. A review of the molecular aspects of melatonin's anti-inflammatory actions: recent insights and new perspectives. Journal of pineal research. 2013;54(1):1\\u0026ndash;14.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eWu HM, Shen QY, Fang L, et al. JNK-TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis. Journal of pineal research. 2016;60(4):415\\u0026ndash;23.\\u003c/span\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cspan\\u003eMarret E, Cinotti R, Berard L, et al. Protective ventilation during anaesthesia reduces major postoperative complications after lung cancer surgery: A double-blind randomised controlled trial. Eur J Anaesthesiol. 2018;35(10):727\\u0026ndash;35.\\u003c/span\\u003e \\u003c/li\\u003e \\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"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\":\"ventilator-induced lung injury, one-lung ventilation, NLRP3 inflammasome, endogenous melatonin, inflammation.\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-52115/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-52115/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eBackground:\\u003c/strong\\u003e Exogenous melatonin exerts a similar effect to protective ventilation on attenuating ventilator-induced lung injury (VILI) by inhibiting NLRP3 inflammasome activation in mouse model. However, the effect of protective ventilation on the production of endogenous melatonin and prognosis in patients undergoing esophageal cancer surgery remains unknown. In this study, we aimed to reveal the effects of protective ventilation on the production of endogenous melatonin, interleukin (IL)-1β, IL-18 and major complications in patients undergoing esophageal cancer surgery. \\u003c/p\\u003e\\u003cp\\u003e\\u003cstrong\\u003eMethods: \\u003c/strong\\u003eEight-eight patients were randomized to receive “conventional” ventilation (Vt=10 mL/kg) or lung protective ventilation [Vt=5 mL/kg along with 5 cm of H\\u003csub\\u003e2\\u003c/sub\\u003eO positive end-expiratory pressure (PEEP)]. IL-1β, IL-18 and melatonin levels in bronchoalveolar lavage fluid (BALF) and serum were measured. Respiratory variables and outcomes were evaluated.\\u003c/p\\u003e\\u003cp\\u003e\\u003cstrong\\u003eResults: \\u003c/strong\\u003eLung protective ventilation decreased the peak airway pressure (Ppeak), plateau airway pressure (Pplat) and driving pressure (ΔP) compared with the “conventional” ventilation group. Lung protective ventilation inhibited polymorphonuclear (PMN) cells invasion into the BALF (P=0.000). Likewise, lung protective ventilation suppressed alveolar and serum IL-1β and IL-18 secretion after mechanical ventilation. Furthermore, lung protective ventilation resulted in a decrease in the inhibition of endogenous MT production compared to “conventional” ventilation (P=0.000). In addition, lung protective ventilation reduced the incidence of postoperative pulmonary complications (P=0.04) and the rate of major postoperative complications (P=0.023).\\u003c/p\\u003e\\u003cp\\u003e\\u003cstrong\\u003eConclusions: \\u003c/strong\\u003eTaken together, lung protective ventilation for esophageal cancer surgery suppressed the secretion of IL-1β, IL-18 and restored the endogenous melatonin level. Meanwhile, lung protective ventilation improved postoperative outcomes after esophageal cancer surgery.\\u003c/p\\u003e\\u003cp\\u003e\\u003cstrong\\u003eTrial registration:\\u003c/strong\\u003e The Chinese Clinical Trial Registry, ChiCTR1900026190. Registered 25 September 2019, http://www.chictr.org.cn/edit.aspx?pid=34677\\u0026amp;htm=4\\u003c/p\\u003e\",\"manuscriptTitle\":\"The Effects of Protective Ventilation on the Production of Endogenous Melatonin and Prognosis in Patients Undergoing Esophageal Cancer Surgery: A Prospective Randomized Double-Blind Controlled Study\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2020-08-13 15:16:22\",\"doi\":\"10.21203/rs.3.rs-52115/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2021-05-18T00:00:00+00:00\",\"index\":1,\"fulltext\":\"Recommendation: Reviewer's comments unavailable pending editorial decision\\n\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2021-05-06T00:00:00+00:00\",\"index\":2,\"fulltext\":\"Recommendation: Reviewer's comments unavailable pending editorial decision\\n\"},{\"type\":\"reviewerAgreed\",\"content\":\"\",\"date\":\"2021-05-01T00:00:00+00:00\",\"index\":2,\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"\",\"date\":\"2021-02-04T00:00:00+00:00\",\"index\":1,\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2020-08-13T12:00:00+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2020-08-12T12:00:00+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvited\",\"content\":\"\",\"date\":\"2020-08-12T12:00:00+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2020-08-12T12:00:00+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"\",\"date\":\"2020-08-01T12:00:00+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"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\":\"cb94041e-5f98-4d53-9c7f-9b013021d0f9\",\"owner\":[],\"postedDate\":\"August 13th, 2020\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"under-review\",\"subjectAreas\":[{\"id\":288329,\"name\":\"Anesthesiology \\u0026 Pain Medicine\"}],\"tags\":[],\"updatedAt\":\"2020-08-13T15:16:22+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2020-08-13 15:16:22\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-52115\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-52115\",\"identity\":\"rs-52115\",\"version\":[\"v1\"]},\"buildId\":\"FbvkV6FR0MCFSLy54lSbu\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}