Effects of esketamine-based anaesthesia on the Systemic Inflammatory Response in Thoracic Surgical Patients: a prospective, single-center, randomized, controlled trial

Effects of esketamine-based anaesthesia on the Systemic Inflammatory Response in Thoracic Surgical Patients: a prospective, single-center, randomized, controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of esketamine-based anaesthesia on the Systemic Inflammatory Response in Thoracic Surgical Patients: a prospective, single-center, randomized, controlled trial Wanxue Song, Xingshuai Huang, Yingke Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2254255/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Thoracic surgery with one-lung ventilation (OLV) leads to a postoperative inflammatory response. In this prospective randomized study, we compared the effect of esketamine-based anaesthesia on perioperative inflammatory cytokine levels in patients under routine anaesthesia with opioids undergoing thoracic surgery with OLV. Methods Adult patients undergoing wedge resections or total lobectomies under video-assisted thoracic surgery (VATS) were randomly assigned (1:1) to receive esketamine-based anaesthesia (Esketamine group, n = 22) or sufentanil-based anaesthesia (Sufentanil group, n = 22). Blood samples for measurement of inflammatory factors were collected from the radial artery at three time points: before anaesthesia induction (T1); 1 h after OLV (T2) and 2 h after surgery (T3). Peripheral venous blood was collected 24 hours before surgery (Preop) and 24 hours after surgery (Postop) to measure leukaemia cell lines and C-reactive protein (CRP). Results Compared with the sufentanil group, the increase in proinflammatory cytokines interleukin (IL)-6 (10.23 ± 5.60 vs. 20.97 ± 18.22 pg/ml, P = 0.029) and IL-8 secretions (4.88 ± 18.29 vs. 81.69 ± 130.34 pg/ml, P = 0.026) was significantly lower in the esketamine group 2 h after the intrathoracic procedure. CRP levels (24.36 ± 12.64 vs. 49.71 ± 29.60 mg/L, P < 0.001) and blood loss volumes (11.14 ± 4.86 ml vs. 28.18 ± 18.16 ml, P < 0.001) were significantly lower in the esketamine group than in the sufentanil group (24.36 ± 12.64 vs. 49.71 ± 29.60, P < 0.001). There was no difference in biometric data, surgical procedures, duration of surgery, OLV and mechanical ventilation, or length of hospital stay among the groups. Conclusions Our study demonstrates that esketamine possesses potent anti-inflammatory properties. Anaesthesia with esketamine may play a beneficial role in reducing both the OLV-induced systemic inflammatory response and intraoperative blood loss. Trial registration: ChiCTR2200065915. Registered on 18/11/2022. anaesthetics esketamine one-lung ventilation immune response thoracic surgery lung protection Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction One-lung ventilation (OLV), a technique to collapse the lung on the side undergoing surgery, is essential for the induction of anaesthesia in patients undergoing thoracic surgery. Nevertheless, OLV influences the production of inflammatory cytokines that regulate the inflammatory response, which is observed during and after lung resection due to increased tidal volume and airway pressure [ 1 ] . Other triggering factors include capillary shear stress because of hyperperfusion, hypoxic pulmonary vasoconstriction, re-expansion of the collapsed lung, oxidative stress-related injury, and ischaemia‒reperfusion injury [ 2 ] . This may be a potential reason why, compared with standard procedures such as intra-abdominal surgery, an inflammatory reaction is more frequent in patients undergoing thoracic surgery under OLV [ 3 ] . Moreover, the perioperative increase in the release of inflammatory cytokines in patients undergoing lung surgery is associated with postoperative complications, such as pneumonia atelectasis and atrial fibrillation [ 4 ] . In addition to OLV, the postoperative systemic inflammatory response is also affected by many factors, such as preoperative lung tissue conditions, surgical procedures, and the influence of anaesthetics [ 5 ] . Ketamine, a classic NmethylDaspartate (NMDA) receptor antagonist, has a significant beneficial effect on the modulation of inflammation. Esketamine, the dextroisomer of racemic ketamine, has four times more affinity to NMDA receptors than its stereoisomer R (-) ketamine, which can dilate bronchioles as well [6] . This NMDA receptor inhibitor acts on the different steps of inflammation regarding inflammatory cell recruitment, inflammatory factor production, and the regulation of inflammatory mediators. These interactions result in the anti-inflammatory effect of esketamine, thus alleviating the increase in systemic inflammation without influencing the local healing process [7] . In a study on patients undergoing coronary artery bypass graft surgery, the administration of esketamine-based anaesthesia was sufficient to reduce the production of inflammatory cytokines [ 8 ] , demonstrating that esketamine possesses anti-inflammatory potential. It, therefore, remains unclear whether continuous esketamine administration during thoracic surgery might attenuate inflammatory cytokine release during and after OLV. In our study, esketamine was the only analgesic administered to patients undergoing video-assisted thoracic surgery (VATS) with OLV. The aim of the study was to establish whether anaesthesia induction and maintenance with esketamine reduces the inflammatory response in patients undergoing thoracic surgery under OLV. We hypothesized that an esketamine-based anaesthetic regimen would be more beneficial for alleviating the inflammatory response in patients undergoing lung resection surgery under OLV. Materials And Methods The study was designed as a prospective, randomized, single-blinded clinical trial and was approved by the Institutional Review Board of Shanghai Changzheng Hospital (2022SL033) and registered in the Chinese Clinical Trial Registry (ChiCTR2200065915). This study was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. Patient Characteristics From July 2022 to October 2022, fifty adult patients scheduled for elective wedge resections as well as total lobectomies under VATS were eligible to participate after we obtained both approval from the local ethics committee and written informed consent from the patients. The exclusion criteria were as follows: body mass index greater than 35 kg/m 2 , history of treatment with immunosuppressive drugs, radiation, and chemotherapy, cardiac insufficiency (New York Heart Association class greater than II), and upper respiratory tract or systemic infection after hospitalization (clinically defined or C-reactive protein concentrations greater than 5 mg/l, white blood cell count > 10.0*10 ^ 9/L, or body temperature higher than 37°C). Patients with intraoperative oxygen saturation (SpO 2 ) that fell below 90% were also excluded. An independent investigator used SPSS Statistics Version 26.0 (IBM Corp, Armonk, New York) to perform simple randomization and inserted the results into opaque, sealed envelopes. The patients were assigned to receive either esketamine (Esketamine group) or sufentanil anaesthesia (Sufentanil group) in a 1:1 ratio. The patients and investigators in charge of the postoperative outcomes assessment were blinded to the assignment. However, for safe individualized treatment, the anaesthesiologists were not blinded to the assignment. Anaesthesia All patients received an intravenous infusion of atropine 3 mg before arrival to the operating room and underwent general anaesthesia combined with an epidural paravertebral nerve block. In the sufentanil group, general anaesthesia was induced with sufentanil (0.25 ~ 0.6 µg/kg), midazolam (1 ~ 3 mg), propofol (1 ~ 2 mg/kg) and cis-atracurium (0.15 ~ 0.2 mg/kg). For maintenance, a continuous inhalation of sevoflurane with a concentration of 1.5%~2% and an infusion of remifentanil (6 µg/kg/h) was administered. In the esketamine group, anaesthesia was induced with esketamine (0.5 mg/kg), midazolam (1 ~ 3 mg), propofol (1 ~ 2 mg/kg), and cis-atracurium (0.15 ~ 0.2 mg/kg). Anaesthesia was maintained by continuous inhalation of sevoflurane at a concentration of 1.5%~2% and infusion of esketamine (0.2 ~ 0.5 mg/kg). The doses of esketamine, opioids, and cis-atracurium were calculated according to the ideal body weight of the patient, and the doses of other drugs were calculated according to the actual body weight. The maintenance dose of drugs was adjusted according to the depth of anaesthesia and the type of surgical procedure. Intermittent intravenous injection of cis-atracurium was used to maintain muscle relaxation according to the need for surgery. If the patient's heart rate was lower than 50 beats/min, atropine was given intravenously. Ephedrine was administered if the patient's systolic blood pressure decreased by more than 30%. All patients received paravertebral nerve block with ropivacaine (0.5%) after anaesthetic induction. A radial artery catheter (B. Braun Melsungen AG, Jakarta Indonesia) and a central venous catheter (Beijing Target Medical Technologies, Inc., Beijing, China) were placed in all the patients. We continuously monitored the electrocardiogram, invasive arterial blood pressure, oxygen saturation, airway pressure, end-expiratory carbon dioxide, and urine volume while the patient was under anaesthesia. Arterial blood gas analyses were performed according to clinical needs. None of our patients received blood transfusions. Airway management and ventilation setup All the patients received a disposable visible double-lumen endobronchial tube (Well Lead Medical Co., Ltd, Guangzhou, China) and were under volume-controlled ventilation. The inspiratory pressure was limited to 30 cmH 2 O. The positive end-expiratory pressure was set to 4 ~ 5 cmH 2 O. The fraction of inspired oxygen (FIO 2 ) was set at 0.5 ~ 0.7 after induction and adjusted to 0.8 ~ 1.0 when patients were placed under OLV to maintain SpO 2 > 90%. The tidal volume was set to 6 ml/kg, and the respiratory rate was adjusted to maintain partial pressure of carbon dioxide (PaCO 2 ) between 35 and 45 mmHg. We inflated the collapsed lung periodically. Primary and secondary outcomes The primary study outcome was the systemic inflammatory response to OLV, as measured by the concentration of serum cytokines: interleukin (IL)-6, IL-8, and IL-10. Secondary outcomes were leukaemia cell lines and C-reactive protein (CRP) level of all the patients. We collected blood samples from the radial artery at three timepoints, before anaesthesia induction (T1), 1 h after OLV (T2) and 2 h after the intrathoracic procedure (T3), to measure inflammatory factors. Peripheral venous blood was collected 24 hours before surgery (Preop) and 24 hours after surgery (Postop) to measure leukaemia cell lines and CRP levels. Sample measurement methods All blood samples were centrifuged at room temperature and 3000 r for 4 min immediately after collection and then immediately stored at -80°C. Plasma concentrations of IL-6, IL-8, and IL-10 were determined using enzyme-linked immunosorbent assay (ELISA) according to manufacturers’ instructions (MultiSciences Biotech Co., Ltd., Hangzhou, Zhejiang, China). Plasma levels of CRP were determined using an immuno-scatter turbidmetry (Lifotronic Technology Co., Ltd., Shenzhen, China). Leukaemia cell lines were determined using a five-classification haematology analyser (Sysmex Corporation, Shanghai, China). Sample size calculation The sample size was calculated based on a previous study [ 8 ] in which researchers compared the concentration of IL-6 the patients under esketamine-based anaesthesia with that of those under sufentanil-based anaesthesia. The sample size was calculated, with a mean of 56.75 and a standard deviation of 46.28 in the esketamine group and a mean of 172.64 and a standard deviation of 149.93 in the sufentanil group; the mean difference was 115.89, with a power of 80%, and an alpha error of 5%. The sample size calculated was at least 15, and we added 3 subjects considering a nonparticipation rate of 20%. The final sample size was at least 18 in each group. Statistical Analysis Statistical analyses were performed using SPSS Statistics Version 26.0. Data were summarized using the mean ± standard deviation in quantitative data and numbers (percentages) for categorical data. Repeated measures ANOVA was used for the comparison of serial measurements within a single group. Data from the two groups were analysed using the paired Student’s t test or Wilcoxon test for quantitative data and the chi-square test for qualitative data. p values below 0.05 were considered statistically significant. Results Patient and perioperative characteristics A total of 50 patients with wedge resections as well as total lobectomies were enrolled in the study: 22 in the sufentanil group and 22 in the esketamine group (Fig. 1). None of these patients had any signs of preoperative pulmonary or systemic infection. There was no difference regarding biometric data, surgical procedures, duration of surgery, OLV and mechanical ventilation (MV), or length of hospital stay between the two groups, however the esketamine group had less blood loss (11.14 ± 4.86 ml) than the sufentanil group (28.18 ± 18.16 ml) (P < 0.001; Table 1 ). Table 1 Patient and perioperative characteristics Sufentanil Esketamine P Biometric Data Age, years 58.77 ± 11.92 58.55 ± 8.69 0.943 Female 17(77%) 14(64%) 0.322 Weight, kg 61.77 ± 8.22 61.68 ± 9.36 0.878 Height, cm 163.41 ± 5.74 164.23 ± 10.07 0.743 BMI, kg/m2 23.15 ± 3.03 22.85 ± 2.72 0.737 Non-smoker 18(82%) 16(73%) 0.472 ASA class I/II/III 1/19/2 0/21/1 0.488 Perioperative Data Procedures 0.131 Pulmonary Lobectomy 9(41%) 14(64%) Wedge-shaped excision of lung 13(59%) 8(36%) Duration of OLV, min 79.59 ± 38.38 65.14 ± 27.32 0.162 Duration of MV, min 121.55 ± 40.59 103.27 ± 30.64 0.12 Duration of Surgery, min 98.77 ± 33.65 82.45 ± 29.87 0.107 Blood loss, ml 28.18 ± 18.16 11.14 ± 4.86 0.000 * Length of hospital stay, days 10.82 ± 3.54 9.77 ± 2.41 0.374 Data are expressed as absolute numbers in mean ± SD or number(percentage). BMI = Body Mass Index, ASA = American Society of Anesthesiologists, OLV = one-lung-ventilation, MV = mechanical ventilation * : P < 0.05 vs the Sufentanil group. Inflammatory response after OLV OLV resulted in an increase in the IL-6 and IL-10 plasma levels in both the sufentanil and the esketamine groups (Figs. 2 and 4). It is worth noting that the concentrations of IL-8 increased in the sufentanil group but decreased significantly in the esketamine group (Fig. 3). No statistically significant difference was detected in the concentration of IL-6, IL-8, or IL-10 between the two groups of patients before anaesthesia induction and 1 h after OLV. However, we observed a significantly diminished postoperative increase in the proinflammatory cytokines, IL-6 (P = 0.029) and IL-8 (P = 0.026), in the esketamine group when compared with the sufentanil group (Figs. 2 and 3) 2 h after the intrathoracic procedure. In addition, patients in the esketamine group showed a higher level of the anti-inflammatory cytokine IL-10 (P = 0.223) 2 h after the intrathoracic procedure, but the difference was not statistically significant (Fig. 4). Blood differential leukocyte count and CRP were assessed preoperatively and postoperatively as additional markers for inflammation. There was no statistically significant difference in CRP or leukocytes between the anaesthesia groups preoperatively (Table 2 ). Postoperative levels of CRP and differential leukocyte count were significantly higher in the two groups when compared with preoperative levels (P < 0.001, Table 2 ), except for the level of lymphocyte count, which was significantly lower postoperatively (P < 0.001, Table 2 ). It is worth noting that CRP, a highly sensitive marker of the acute system response, was significantly lower in the esketamine group than in the sufentanil group (P < 0.001, Table 2 and Fig. 5). Table 2 Inflammatory cells Sufentanil Esketamine P WBC(*10 ^ 9/L) Pre-op 5.85 ± 1.10 5.49 ± 1.32 0.312 Post-op 12.60 ± 2.6 * 12.08 ± 3.04 * 0.541 MONO(*10 ^ 9/L) Pre-op 0.44 ± 0.84 0.41 ± 0.13 0.353 Post-op 0.83 ± 0.25 * 0.85 ± 0.36 * 0.681 LY(*10 ^ 9/L) Pre-op 1.89 ± 0.44 1.76 ± 0.48 0.17 Post-op 1.08 ± 0.33 * 1.00 ± 0.40 * 0.285 NEUT(*10 ^ 9/L) Pre-op 3.33 ± 0.91 3.10 ± 0.89 0.46 Post-op 10.64 ± 2.65 * 10.20 ± 2.76 * 0.681 CRP (mg/L) Pre-op 1.88 ± 1.89 1.75 ± 2.86 0.858 Post-op 49.71 ± 29.60 * 24.36 ± 12.64 * 0.001 # WBC = white blood cell count, MONO = monocyte count, LY = lymphocyte count, NEUT = neutrophil count, CRP = C-reaction protein, Pre-op = preoperation, Post-op = postoperation * Differences within the single study group (P < 0.001). # Differences between the sufentanil and esketamine anaesthesia patient Discussion The main finding of the study is that esketamine used as the sole analgesic during thoracic surgery reduces the release of the proinflammatory cytokine associated with OLV. Furthermore, compared with sufentanil-based anaesthesia, esketamine may also be able to alleviate the systemic inflammatory response postoperatively, as was suggested by the lower level of CRP 24 hours after surgery. Thoracic surgery, including oesophagectomy and lobectomy, induces a more severe systemic inflammatory reaction than other routine surgeries [ 3 ] . This is most likely due to the use of OLV during thoracic procedures. Mechanical ventilation itself may induce pulmonary damage due to high inspiratory pressure and shear forces following the opening and collapse of alveoli [ 9 ] . Ventilation-induced injury is further amplified by the OLV strategy, which collapses the surgically treated lung and delivers the whole tidal volume to the other lung [ 10 ] . Surgical manipulation, lung collapse and re-expansion [ 11 ] , high oxygen tension [ 12 ] , and capillary shear stress because of hyperperfusion [ 13 ] or high tidal volumes and increased airway pressures [ 14 ] during OLV may cause further pulmonary damage, thus inducing systemic proinflammatory responses. In addition, during the OLV period, the collapsed lung is in a state of hypoxia, and subsequently, hypoxic pulmonary vasoconstriction (HPV) occurs. Therefore, another possible reason lung injury induced by OLV is vascular endothelial damage following reperfusion injury in areas of prior hypoxic constriction, with the resulting reactive oxygen species disrupting the permeability of the vascular endothelium. Ventilation-induced pulmonary injury is characterized by alveolar wall disruption, immune cell recruitment, inflammatory cytokine production, excessive reactive oxygen species production, and oedema formation [ 15 ] . First, inflammatory cells such as lymphocytes, macrophages, and neutrophils produce cytokines in an autocrine way, and then the alveolar epithelial cells, fibroblast cells, and endothelial cells produce more cytokines in a paracrine manner, forming a “waterfall” effect. Although the initial step of this process is limiting inflammation locally to alleviate pulmonary symptoms, this response can progress to systemic inflammation. The excessive secretion of proinflammatory cytokines is detrimental to the proper functioning of the organism, leading to a loss of organ function and potential multiorgan failure. Appropriate inhibition of the inflammatory response is conducive to the recovery of patients, thus reducing the occurrence of complications, which is also a requirement for fast-track surgery. The normal concentration of these cytokines is necessary for the physiological function of the immune system. However, an intuitive way to detect cytokine changes during lung injury is to examine them in bronchoalveolar lavage (BAL) fluid. However, Douzinas et al. found that the levels of IL-1β and IL-6 in the arterial blood of acute respiratory distress syndrome (ARDS) patients increased, suggesting that the lung injury of these patients was involved in the release of cytokines into the systemic circulation [ 16 ] . Moreover, they pointed out that the concentration of cytokines in arterial blood was higher than that in venous blood and was closer to those in the lung. In addition, interindividual differences were apparent in the alveolar lavage fluid but less so in blood. Therefore, in this study, we were inclined to determine the concentrations of IL-6, IL-8, and IL-10 in the arterial blood of patients to indicate the degree of OLV-induced lung injury, which is more practical in clinical research. Several experimental and clinical studies have shown that the selection of anaesthetic agents may have an impact on the immune system. Some anaesthetic protocols may be involved in immunosuppressive effects. Ketamine, a noncompetitive NMDA receptor antagonist, is known to produce increases in blood pressure and stroke volume, which enables it to be broadly applied in clinical practice. It has also been shown to possess anti-inflammatory effects, probably related to inflammatory cell recruitment, the regulation of inflammatory mediators, and the secretion of inflammatory cytokines. In vitro and in vivo data from several studies indicate that ketamine suppresses the function of lymphocytes, neutrophils, and natural killer cells [ 7 ] . Furthermore, Weigand et al. demonstrated that racemic ketamine and its isomers esketamine and R(-)ketamine have comparable inhibitory effects, implying that the suppression of irritated neutrophil function is probably not mediated by receptor-specific interactions [ 17 ] . Wu et al. proposed that ketamine decreased tumour necrosis factor (TNF)-α and IL-6 biosynthesis in lipopolysaccharide-activated macrophages through inhibition of activator protein-1 translocation and Toll-like receptor 4-dependent Jun N-terminal kinase activation [ 18 ] . Furthermore, Chen et al. found that ketamine remarkably prohibits lipopolysaccharide-induced nuclear factor-κB (NF-κB) translocation and transcriptional activation, thereby diminishing the production of TNF-α, IL-1β and IL-6 [ 19 ] . Thus, there is accumulating evidence that ketamine can inhibit signalling pathways and transcription factors for proinflammatory cytokines to reduce the release of these cytokines. However, the anti-inflammatory mechanism of esketamine remains uncertain and requires extensive experimental evidence. A key finding from our studies is that, compared with sufentanil-based analgesia, esketamine as the sole analgesic is better at alleviating IL-6 and IL-8 release at 2 h after the intrathoracic procedure, when the release of inflammatory cytokines is higher than other times in patients undergoing thoracic surgery with OLV [ 20 ] . In a study of patients undergoing coronary artery bypass grafting with extracorporeal circulation, the patients in whom anaesthesia was induced and maintained with esketamine had significantly lower increases in the proinflammatory cytokines IL-6 and IL-8 6 h after the opening of the aorta than those in the sufentanil group, while the anti-inflammatory cytokine IL-10 showed higher levels in the esketamine group, thus suggesting that esketamine has similar anti-inflammatory properties [ 8 ] . A recent study has shown that subanesthetic esketamine administered at the induction of anaesthesia was more conducive in relieving the inflammatory response in elderly surgical patients based on its lower increase in CRP, procalcitonin, and the white blood cell count in blood than sufentanil [ 21 ] . However, in this study, esketamine was used as an adjunct to sufentanil-based anaesthesia. All these studies suggest that esketamine has beneficial effects on the immune response in the perioperative period of different procedures, which is consistent with our findings. Of note, Wang et al. also reported that the administration of low-dose ketamine to patients with acute lung injury resulting from mechanical ventilation could significantly decrease inflammatory factors such as IL-1β, Caspase-1, and NF-κB [ 22 ] . In addition to the anti-inflammatory effects mentioned above, this study also indicated that ketamine could improve the pulmonary ventilation and gas exchange function of patients, shorten the time of the ventilation, improve the success rate of deconditioning, and reduce the mortality rate. Not only does this illustrate the benefit of ketamine in alleviating the inflammatory response in patients with lung injury, it also provides additional evidence that its use in patients with lung injury has a facilitative role in their recovery. Increased expression of proinflammatory cytokines, especially IL-6 and IL-8, after lung resection is associated with increases in the incidence of postoperative complications (atelectasis, pneumonia, pleural empyema, atrial fibrillation, etc.) [ 4 ] and the systemic inflammatory response, which are predictors of length of hospital stay [ 23 ] . IL-6 is a modulator of the immune response, acute-phase response, and haematopoiesis produced by lymphocytes or nongonadal cells. Sparrow et al. noted that the suppression of systemic IL-6 significantly mitigated neuronal injury in the frontal cortex and hippocampus in mice after MV [ 24 ] , suggesting that in addition to lung injury and pulmonary complications, IL-6 is related to ventilator-induced neuronal injury. This would further indicate that the reduction in IL-6 levels in our findings is of significant importance and provides strong support for the clinical use of esketamine during OLV. IL-8 is considered a specific cytokine of the pulmonary inflammatory response and tissue injury, which can reflect the degree of lung injury. The concentration of IL-8 was found to be significantly elevated in the BAL fluid of ARDS patients, and patients with high IL-8 concentrations in the BAL fluid had higher death rates than those with lower concentrations [ 25 ] . It should be noted that the concentrations of IL-8 were elevated in the sufentanil group and decreased in the esketamine group in our study. Several clinical studies have shown that mechanical ventilation induces an increase in IL-8 in both the lungs and the circulatory system [ 26 – 28 ] . Nevertheless, we found a significant decrease in IL-8 levels in the esketamine group, suggesting that esketamine-based anaesthesia has an efficient effect on decreasing IL-8 release during thoracic surgery. Therefore, based on our findings, we suggest that the administration of esketamine for anaesthesia has potential anti-inflammatory effects, which are beneficial for reducing the incidence of postoperative pulmonary complications and alleviating perioperative lung injury induced by surgery and mechanical ventilation in patients under OLV during surgery. However, in our study, although patients in the esketamine group had a higher concentration of postoperative IL-10 than those in the sufentanil group, the result was not statistically significant. IL-10 is a cytokine with a promising anti-inflammatory effect that not only directly inhibits the inflammatory response itself but also alleviates the tissue damage triggered by inflammation. An endotoxin study in a rat model of acute lung injury discovered that exogenous IL-10 can attenuate lung injury by reducing proinflammatory cytokines in pulmonary tissue [ 29 ] . Chen et al. investigated whether IL-10 alleviates mechanical ventilation-induced pulmonary injury through two major routes: the oxidative stress pathway and the inflammatory response pathway [ 30 ] . However, in our study, we found no effect of ketamine on IL-10. Further detailed studies are therefore needed to identify the primary effect of esketamine on the production of IL-10 during thoracic surgery. Moreover, we have also found that esketamine has the potential to alleviate the postoperative systemic inflammatory response, as was suggested by the lower level of CRP 24 hours after surgery compared with sufentanil-based anaesthesia. CRP is a general indicator of inflammation created by the liver as a response to cytokines involved in physical stress, necrosis, or infection. The higher the perioperative CRP level, the worse the prognosis, regardless of whether serious postoperative complications develop. CRP is a particularly sensitive but nonspecific sign of the acute phase response [ 31 ] . Okada et al. prospectively analysed 356 patients who underwent lobectomy and identified significantly poorer overall survival and recurrence-free survival in patients with higher perioperative CRP [ 32 ] . Similarly, Hara et al. revealed that patients with lower postoperative CRP levels undergoing radical surgery for non-small cell lung cancer had significantly higher 5-year disease recurrence, survival and overall survival rates than those with higher levels [ 33 ] . Based on this finding, we suggest that the use of ketamine in thoracic surgery may reduce the acute postoperative inflammatory response and thus reduce the risk of postoperative mortality. In addition to the anti-inflammatory effect, a significant reduction in blood loss was observed in the esketamine group. Intraoperative blood loss is usually due to the oozing of blood from the wound vein, and arterial bleeding is usually obvious and quickly stopped [ 34 ] . We believe that the reduction in blood loss observed in our study may be related to the more stable haemodynamics resulting from esketamine anaesthesia. Unfortunately, intraoperative haemodynamics were not recorded in our study. However, in another study, Li et al. found that low-dose esketamine for anaesthesia in elderly patients undergoing knee arthroplasty may better maintain the stability of haemodynamics [ 35 ] . Reduced bleeding decreases the need for allogeneic blood transfusions and autologous blood transfusions, resulting in faster postoperative recovery and fewer complications [ 36 ] . Therefore, the use of esketamine for anaesthesia can not only alleviate the postoperative inflammatory response but also reduce intraoperative blood loss and further reduce the risk of perioperative complications of patients. Several limitations of this study were noted. First, the study was performed at a single centre, indicating that the results are reflective of clinical practice at the authors' institution and are not generalizable. Second, this strategy permits the use of other intravenous anaesthetics (e.g., dexmedetomidine and midazolam) and inhaled anaesthetics (sevoflurane), which is similar to actual clinical practice, and outcomes can be impacted by these drugs. Although the administration of other anaesthetic agents was similar in the two groups, the authors could not rule out the effect of the interaction of the drugs. Moreover, the most noteworthy limitation of this study is the short-term postoperative observational period. The long-term effects of intraoperative anaesthetic drugs remain to be elucidated. Conclusions In conclusion, our results demonstrate that OLV induces the production and release of inflammatory cytokines into the bloodstream in patients undergoing thoracic surgery. The administration of esketamine, as a sole analgesic, suppresses the systemic inflammatory response in patients undergoing thoracic surgery with OLV and alleviates the effects on serum IL-6 and IL-8 expression. Thus, esketamine has a prospective impact on reducing inflammation related to OLV and intraoperative blood loss in patients undergoing thoracic surgery. Esketamine in thoracic surgery appears to be more beneficial than opioids. Further studies are needed to demonstrate the anti-inflammatory and other advantages of esketamine application in patients undergoing thoracic surgery under OLV. Abbreviations OLV one-lung ventilation VATS video-assisted thoracic surgery CRP C-reactive protein NMDA N-methyl-D-aspartate SpO 2 oxygen saturation FIO 2 inspired oxygen PaCO 2 partial pressure of carbon dioxide IL interleukin MV mechanical ventilation HPV hypoxic pulmonary vasoconstriction BAL bronchoalveolar lavage ARDS acute respiratory distress syndrome TNF tumor necrosis factor NF-κB nuclear factor-κB. Declarations Ethics approval and consent to participate The study was approved by the Institutional Review Board of Shanghai Changzheng Hospital on March 30, 2022, under the reference 2022SL033 and carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. Written informed consent was obtained from all patients. The trial was retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR2200065915, date of registration: 2022-11-18). Consent for publication Not applicable. Availability of data and materials The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding The authors received no funding for this work. Authors’ contributions All authors read and approved the final manuscript. Song WX helped supervise the data collection, analyze the data, prepared, drafted, and reviewed the manuscript; Huang XS helped supervise the data collection, reviewed the literature, and provided surgical content expertise; Li YK helped provided anaesthesiology content expertise, supervised the data collection analyzed the data, edited the final manuscript. Acknowledgment Not applicable. References Sugasawa Y, Yamaguchi K, Kumakura S, Murakami T, Kugimiya T, Suzuki K, Nagaoka I, Inada E: The effect of one-lung ventilation upon pulmonary inflammatory responses during lung resection . J Anesth 2011, 25 (2):170-177. Lohser J, Slinger P: Lung Injury After One-Lung Ventilation: A Review of the Pathophysiologic Mechanisms Affecting the Ventilated and the Collapsed Lung . Anesth Analg 2015, 121 (2):302-318. Sakamoto K, Arakawa H, Mita S, Ishiko T, Ikei S, Egami H, Hisano S, Ogawa M: Elevation of circulating interleukin 6 after surgery: factors influencing the serum level . 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Welters ID, Feurer MK, Preiss V, Müller M, Scholz S, Kwapisz M, Mogk M, Neuhäuser C: Continuous S-(+)-ketamine administration during elective coronary artery bypass graft surgery attenuates pro-inflammatory cytokine response during and after cardiopulmonary bypass . Br J Anaesth 2011, 106 (2):172-179. Steinberg JM, Schiller HJ, Halter JM, Gatto LA, Lee HM, Pavone LA, Nieman GF: Alveolar instability causes early ventilator-induced lung injury independent of neutrophils . Am J Respir Crit Care Med 2004, 169 (1):57-63. Kozian A, Schilling T, Röcken C, Breitling C, Hachenberg T, Hedenstierna G: Increased alveolar damage after mechanical ventilation in a porcine model of thoracic surgery . J Cardiothorac Vasc Anesth 2010, 24 (4):617-623. Funakoshi T, Ishibe Y, Okazaki N, Miura K, Liu R, Nagai S, Minami Y: Effect of re-expansion after short-period lung collapse on pulmonary capillary permeability and pro-inflammatory cytokine gene expression in isolated rabbit lungs . Br J Anaesth 2004, 92 (4):558-563. Olivant Fisher A, Husain K, Wolfson MR, Hubert TL, Rodriguez E, Shaffer TH, Theroux MC: Hyperoxia during one lung ventilation: inflammatory and oxidative responses . Pediatr Pulmonol 2012, 47 (10):979-986. Kozian A, Schilling T, Fredén F, Maripuu E, Röcken C, Strang C, Hachenberg T, Hedenstierna G: One-lung ventilation induces hyperperfusion and alveolar damage in the ventilated lung: an experimental study . Br J Anaesth 2008, 100 (4):549-559. Nin N, Peñuelas O, de Paula M, Lorente JA, Fernández-Segoviano P, Esteban A: Ventilation-induced lung injury in rats is associated with organ injury and systemic inflammation that is attenuated by dexamethasone . Crit Care Med 2006, 34 (4):1093-1098. Schilling T, Kozian A, Huth C, Bühling F, Kretzschmar M, Welte T, Hachenberg T: The pulmonary immune effects of mechanical ventilation in patients undergoing thoracic surgery . Anesth Analg 2005, 101 (4):957-965. Douzinas EE, Tsidemiadou PD, Pitaridis MT, Andrianakis I, Bobota-Chloraki A, Katsouyanni K, Sfyras D, Malagari K, Roussos C: The regional production of cytokines and lactate in sepsis-related multiple organ failure . Am J Respir Crit Care Med 1997, 155 (1):53-59. Weigand MA, Schmidt H, Zhao Q, Plaschke K, Martin E, Bardenheuer HJ: Ketamine modulates the stimulated adhesion molecule expression on human neutrophils in vitro . Anesth Analg 2000, 90 (1):206-212. Wu GJ, Chen TL, Ueng YF, Chen RM: Ketamine inhibits tumor necrosis factor-alpha and interleukin-6 gene expressions in lipopolysaccharide-stimulated macrophages through suppression of toll-like receptor 4-mediated c-Jun N-terminal kinase phosphorylation and activator protein-1 activation . Toxicol Appl Pharmacol 2008, 228 (1):105-113. Chen TL, Chang CC, Lin YL, Ueng YF, Chen RM: Signal-transducing mechanisms of ketamine-caused inhibition of interleukin-1 beta gene expression in lipopolysaccharide-stimulated murine macrophage-like Raw 264.7 cells . Toxicol Appl Pharmacol 2009, 240 (1):15-25. HUANG Bing, HE Binghua, PAN Linghun,HUANG Yanjuan: Changes of TNF-α, IL-6 and IL-8 in patients undergoing lobectomy with one-lung ventilation . J Clin Anesthesiol 2008, 24 (12):1017-1019. Tu W, Yuan H, Zhang S, Lu F, Yin L, Chen C, Li J: Influence of anesthetic induction of propofol combined with esketamine on perioperative stress and inflammatory responses and postoperative cognition of elderly surgical patients . Am J Transl Res 2021, 13 (3):1701-1709. Wang WF, Liu S, Xu B: A study of the protective effect and mechanism of ketamine on acute lung injury induced by mechanical ventilation . Eur Rev Med Pharmacol Sci 2017, 21 (6):1362-1367. Sugita J, Fujiu K: Systemic Inflammatory Stress Response During Cardiac Surgery . Int Heart J 2018, 59 (3):457-459. Sparrow NA, Anwar F, Covarrubias AE, Rajput PS, Rashid MH, Nisson PL, Gezalian MM, Toossi S, Ayodele MO, Karumanchi SA et al : IL-6 Inhibition Reduces Neuronal Injury in a Murine Model of Ventilator-induced Lung Injury . Am J Respir Cell Mol Biol 2021, 65 (4):403-412. Allen TC, Kurdowska A: Interleukin 8 and acute lung injury . Arch Pathol Lab Med 2014, 138 (2):266-269. Nakamura M, Fujishima S, Sawafuji M, Ishizaka A, Oguma T, Soejima K, Matsubara H, Tasaka S, Kikuchi K, Kobayashi K et al : Importance of interleukin-8 in the development of reexpansion lung injury in rabbits . Am J Respir Crit Care Med 2000, 161 (3 Pt 1):1030-1036. Ju NY, Gao H, Huang W, Niu FF, Lan WX, Li F, Gao W: Therapeutic effect of inhaled budesonide (Pulmicort® Turbuhaler) on the inflammatory response to one-lung ventilation . Anaesthesia 2014, 69 (1):14-23. Schilling T, Kozian A, Senturk M, Huth C, Reinhold A, Hedenstierna G, Hachenberg T: Effects of volatile and intravenous anaesthesia on the alveolar and systemic inflammatory response in thoracic surgical patients . anaesthesiology 2011, 115 (1):65-74. Escofier N, Boichot E, Germain N, Silva PM, Martins MA, Lagente V: Effects of interleukin-10 and modulators of cyclic AMP formation on endotoxin-induced inflammation in rat lung . Fundam Clin Pharmacol 1999, 13 (1):96-101. Chen J, Lin J, Luo H, Li M: Effects of Human Interleukin-10 on Ventilator-Associated Lung Injury in Rats . Inflammation 2019, 42 (2):538-547. Lopez-Pastorini A, Riedel R, Koryllos A, Beckers F, Ludwig C, Stoelben E: The impact of preoperative elevated serum C-reactive protein on postoperative morbidity and mortality after anatomic resection for lung cancer . Lung Cancer 2017, 109 :68-73. Okada S, Shimomura M, Tsunezuka H, Teramukai S, Ishihara S, Shimada J, Inoue M: Prognostic Significance of Perioperative C-Reactive Protein in Resected Non-Small Cell Lung Cancer . Semin Thorac Cardiovasc Surg 2020, 32 (4):1046-1055. Hara M, Yonei A, Ayabe T, Tomita M, Nakamura K, Onitsuka T: Postoperative serum C-reactive protein levels in non-small cell lung cancer patients . Ann Thorac Cardiovasc Surg 2010, 16 (2):85-90. Davies MJ: Minimising intra-operative blood loss . Transfus Apher Sci 2002, 27 (1):55-57. Li J, Wang Z, Wang A, Wang Z: Clinical effects of low-dose esketamine for anaesthesia induction in the elderly: A randomized controlled trial . J Clin Pharm Ther 2022, 47 (6):759-766. Matsuura N, Okamura T, Ide S, Ichinohe T: Remifentanil Reduces Blood Loss During Orthognathic Surgery . Anesth Prog 2017, 64 (1):3-7. Additional Declarations No competing interests reported. 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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-2254255","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":155849059,"identity":"846a50e5-4553-4364-9c09-92f94794cae7","order_by":0,"name":"Wanxue Song","email":"","orcid":"","institution":"Shanghai Changzheng Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wanxue","middleName":"","lastName":"Song","suffix":""},{"id":155849060,"identity":"ecf252c1-cee4-424e-afa4-0ab9dde37ef2","order_by":1,"name":"Xingshuai Huang","email":"","orcid":"","institution":"Shanghai Changzheng Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xingshuai","middleName":"","lastName":"Huang","suffix":""},{"id":155849061,"identity":"4f2bf4bb-2395-4229-9baf-5d2fb6bfe4e2","order_by":2,"name":"Yingke Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3ElEQVRIiWNgGAWjYBACPmYGhgMMDAkM/BJgvoQMQS1sMC2SMxgYG4BaeAhrgVAJDAY3wFoYiNDCzmN4uOBXmpzx7ebjj27UWPAwsB8+ugG/w3gMDs/syzE2u3MssTnnGNBhPGlpNwhq4e2pSNx2I8ewOYcNqEWCx4woLfWbZ4C0/CNWC8+PnAQDCaCW3DaitLAVHOZtSDOccSMtcXZunwQPGyG/8PMf3vyZ50+yPP+M5AOfc77VyfGzHz6GVwsDA4cBA2Mbsr34lYMA+wMGhj+ElY2CUTAKRsEIBgCUpUPXzanXCgAAAABJRU5ErkJggg==","orcid":"","institution":"The PLA Naval Medical University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yingke","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2022-11-09 08:29:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2254255/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2254255/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":29788956,"identity":"a804332c-5d50-4c5c-8bd9-bfb1e8f24559","added_by":"auto","created_at":"2022-12-01 19:04:29","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":81750,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patient recruitment.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2254255/v1/7f23c717b1db103195512b16.jpg"},{"id":29788760,"identity":"8bf509ad-54d2-42c8-a2ac-7f0dba292d5f","added_by":"auto","created_at":"2022-12-01 19:04:14","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":53202,"visible":true,"origin":"","legend":"\u003cp\u003eIL-6 plasma levels are presented as box plots for each group and time point. The symbol * indicates differences within a single study group, and # marks differences between the sufentanil and esketamine anaesthesia patient.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2254255/v1/566842c6859caac6d8b75629.jpg"},{"id":29788771,"identity":"326e3c8d-c020-4172-8bf1-a252e181eb7f","added_by":"auto","created_at":"2022-12-01 19:04:15","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":46817,"visible":true,"origin":"","legend":"\u003cp\u003eIL-8 plasma levels are presented as box plots for each group and time point. The symbol * indicates differences within a single study group, and # marks differences between the sufentanil and esketamine anaesthesia patient.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2254255/v1/f306a6fe482f85bf70aaee78.jpg"},{"id":29788763,"identity":"f9b355e5-8dad-462f-b8aa-cfb44240c8ce","added_by":"auto","created_at":"2022-12-01 19:04:14","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":38773,"visible":true,"origin":"","legend":"\u003cp\u003eIL-10 plasma levels are presented as box plots for each group and time point. The symbol * indicates differences within a single study group, and # marks differences between the sufentanil and esketamine anaesthesia patient.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2254255/v1/08146eab7349338575309e72.jpg"},{"id":29788921,"identity":"0fd3c6dd-258f-4b98-8f4a-65c5f8681008","added_by":"auto","created_at":"2022-12-01 19:04:27","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":46292,"visible":true,"origin":"","legend":"\u003cp\u003eCRP plasma levels are presented as box plots for each group and time point.\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2254255/v1/74ef2338698898b17a1dc8ee.jpg"},{"id":33050328,"identity":"836866d0-685e-4168-a92c-97b58a847584","added_by":"auto","created_at":"2023-02-16 20:29:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1367740,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2254255/v1/6b1e13bb-227a-4750-bc2f-7278c8278514.pdf"},{"id":29788768,"identity":"8dc40988-27d1-426c-acb6-d9e3f3039066","added_by":"auto","created_at":"2022-12-01 19:04:15","extension":"doc","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":206336,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORTChecklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-2254255/v1/39d754ca99412b1b7b2c3c84.doc"},{"id":29788802,"identity":"640cb917-5981-4add-9b9b-aa47f54a7deb","added_by":"auto","created_at":"2022-12-01 19:04:20","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":35487,"visible":true,"origin":"","legend":"","description":"","filename":"Researchprotocol.docx","url":"https://assets-eu.researchsquare.com/files/rs-2254255/v1/ed562773e8f77ab9a1710071.docx"},{"id":29788791,"identity":"0b60216e-5ce0-4e2e-bb89-e97d9513185e","added_by":"auto","created_at":"2022-12-01 19:04:18","extension":"xlsx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":21214,"visible":true,"origin":"","legend":"","description":"","filename":"originaldata.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-2254255/v1/3a33d6e9753586b27d526876.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of esketamine-based anaesthesia on the Systemic Inflammatory Response in Thoracic Surgical Patients: a prospective, single-center, randomized, controlled trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOne-lung ventilation (OLV), a technique to collapse the lung on the side undergoing surgery, is essential for the induction of anaesthesia in patients undergoing thoracic surgery. Nevertheless, OLV influences the production of inflammatory cytokines that regulate the inflammatory response, which is observed during and after lung resection due to increased tidal volume and airway pressure\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Other triggering factors include capillary shear stress because of hyperperfusion, hypoxic pulmonary vasoconstriction, re-expansion of the collapsed lung, oxidative stress-related injury, and ischaemia‒reperfusion injury\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. This may be a potential reason why, compared with standard procedures such as intra-abdominal surgery, an inflammatory reaction is more frequent in patients undergoing thoracic surgery under OLV \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Moreover, the perioperative increase in the release of inflammatory cytokines in patients undergoing lung surgery is associated with postoperative complications, such as pneumonia atelectasis and atrial fibrillation\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. In addition to OLV, the postoperative systemic inflammatory response is also affected by many factors, such as preoperative lung tissue conditions, surgical procedures, and the influence of anaesthetics\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eKetamine, a classic NmethylDaspartate (NMDA) receptor antagonist, has a significant beneficial effect on the modulation of inflammation. Esketamine, the dextroisomer of racemic ketamine, has four times more affinity to NMDA receptors than its stereoisomer R (-) ketamine, which can dilate bronchioles as well\u003csup\u003e[6]\u003c/sup\u003e. This NMDA receptor inhibitor acts on the different steps of inflammation regarding inflammatory cell recruitment, inflammatory factor production, and the regulation of inflammatory mediators. These interactions result in the anti-inflammatory effect of esketamine, thus alleviating the increase in systemic inflammation without influencing the local healing process\u003csup\u003e[7]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn a study on patients undergoing coronary artery bypass graft surgery, the administration of esketamine-based anaesthesia was sufficient to reduce the production of inflammatory cytokines\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, demonstrating that esketamine possesses anti-inflammatory potential.\u003c/p\u003e \u003cp\u003eIt, therefore, remains unclear whether continuous esketamine administration during thoracic surgery might attenuate inflammatory cytokine release during and after OLV. In our study, esketamine was the only analgesic administered to patients undergoing video-assisted thoracic surgery (VATS) with OLV. The aim of the study was to establish whether anaesthesia induction and maintenance with esketamine reduces the inflammatory response in patients undergoing thoracic surgery under OLV. We hypothesized that an esketamine-based anaesthetic regimen would be more beneficial for alleviating the inflammatory response in patients undergoing lung resection surgery under OLV.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003e The study was designed as a prospective, randomized, single-blinded clinical trial and was approved by the Institutional Review Board of Shanghai Changzheng Hospital (2022SL033) and registered in the Chinese Clinical Trial Registry\u003c/p\u003e \u003cp\u003e(ChiCTR2200065915). This study was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient Characteristics\u003c/h2\u003e \u003cp\u003e From July 2022 to October 2022, fifty adult patients scheduled for elective wedge resections as well as total lobectomies under VATS were eligible to participate after we obtained both approval from the local ethics committee and written informed consent from the patients. The exclusion criteria were as follows: body mass index greater than 35 kg/m\u003csup\u003e2\u003c/sup\u003e, history of treatment with immunosuppressive drugs, radiation, and chemotherapy, cardiac insufficiency (New York Heart Association class greater than II), and upper respiratory tract or systemic infection after hospitalization (clinically defined or C-reactive protein concentrations greater than 5 mg/l, white blood cell count\u0026thinsp;\u0026gt;\u0026thinsp;10.0*10\u003csup\u003e^\u003c/sup\u003e9/L, or body temperature higher than 37\u0026deg;C). Patients with intraoperative oxygen saturation (SpO\u003csub\u003e2\u003c/sub\u003e) that fell below 90% were also excluded.\u003c/p\u003e \u003cp\u003eAn independent investigator used SPSS Statistics Version 26.0 (IBM Corp, Armonk, New York) to perform simple randomization and inserted the results into opaque, sealed envelopes. The patients were assigned to receive either esketamine (Esketamine group) or sufentanil anaesthesia (Sufentanil group) in a 1:1 ratio. The patients and investigators in charge of the postoperative outcomes assessment were blinded to the assignment. However, for safe individualized treatment, the anaesthesiologists were not blinded to the assignment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAnaesthesia\u003c/h2\u003e \u003cp\u003eAll patients received an intravenous infusion of atropine 3 mg before arrival to the operating room and underwent general anaesthesia combined with an epidural paravertebral nerve block. In the sufentanil group, general anaesthesia was induced with sufentanil (0.25\u0026thinsp;~\u0026thinsp;0.6 \u0026micro;g/kg), midazolam (1\u0026thinsp;~\u0026thinsp;3 mg), propofol (1\u0026thinsp;~\u0026thinsp;2 mg/kg) and cis-atracurium (0.15\u0026thinsp;~\u0026thinsp;0.2 mg/kg). For maintenance, a continuous inhalation of sevoflurane with a concentration of 1.5%~2% and an infusion of remifentanil (6 \u0026micro;g/kg/h) was administered. In the esketamine group, anaesthesia was induced with esketamine (0.5 mg/kg), midazolam (1\u0026thinsp;~\u0026thinsp;3 mg), propofol (1\u0026thinsp;~\u0026thinsp;2 mg/kg), and cis-atracurium (0.15\u0026thinsp;~\u0026thinsp;0.2 mg/kg). Anaesthesia was maintained by continuous inhalation of sevoflurane at a concentration of 1.5%~2% and infusion of esketamine (0.2\u0026thinsp;~\u0026thinsp;0.5 mg/kg). The doses of esketamine, opioids, and cis-atracurium were calculated according to the ideal body weight of the patient, and the doses of other drugs were calculated according to the actual body weight. The maintenance dose of drugs was adjusted according to the depth of anaesthesia and the type of surgical procedure. Intermittent intravenous injection of cis-atracurium was used to maintain muscle relaxation according to the need for surgery. If the patient's heart rate was lower than 50 beats/min, atropine was given intravenously. Ephedrine was administered if the patient's systolic blood pressure decreased by more than 30%. All patients received paravertebral nerve block with ropivacaine (0.5%) after anaesthetic induction.\u003c/p\u003e \u003cp\u003eA radial artery catheter (B. Braun Melsungen AG, Jakarta Indonesia) and a central venous catheter (Beijing Target Medical Technologies, Inc., Beijing, China) were placed in all the patients. We continuously monitored the electrocardiogram, invasive arterial blood pressure, oxygen saturation, airway pressure, end-expiratory carbon dioxide, and urine volume while the patient was under anaesthesia. Arterial blood gas analyses were performed according to clinical needs. None of our patients received blood transfusions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAirway management and ventilation setup\u003c/h2\u003e \u003cp\u003eAll the patients received a disposable visible double-lumen endobronchial tube (Well Lead Medical Co., Ltd, Guangzhou, China) and were under volume-controlled ventilation. The inspiratory pressure was limited to 30 cmH\u003csub\u003e2\u003c/sub\u003eO. The positive end-expiratory pressure was set to 4\u0026thinsp;~\u0026thinsp;5 cmH\u003csub\u003e2\u003c/sub\u003eO. The fraction of inspired oxygen (FIO\u003csub\u003e2\u003c/sub\u003e) was set at 0.5\u0026thinsp;~\u0026thinsp;0.7 after induction and adjusted to 0.8\u0026thinsp;~\u0026thinsp;1.0 when patients were placed under OLV to maintain SpO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;90%. The tidal volume was set to 6 ml/kg, and the respiratory rate was adjusted to maintain partial pressure of carbon dioxide (PaCO\u003csub\u003e2\u003c/sub\u003e) between 35 and 45 mmHg. We inflated the collapsed lung periodically.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePrimary and secondary outcomes\u003c/h2\u003e \u003cp\u003eThe primary study outcome was the systemic inflammatory response to OLV, as measured by the concentration of serum cytokines: interleukin (IL)-6, IL-8, and IL-10. Secondary outcomes were leukaemia cell lines and C-reactive protein (CRP) level of all the patients. We collected blood samples from the radial artery at three timepoints, before anaesthesia induction (T1), 1 h after OLV (T2) and 2 h after the intrathoracic procedure (T3), to measure inflammatory factors. Peripheral venous blood was collected 24 hours before surgery (Preop) and 24 hours after surgery (Postop) to measure leukaemia cell lines and CRP levels.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eSample measurement methods\u003c/h2\u003e \u003cp\u003eAll blood samples were centrifuged at room temperature and 3000 r for 4 min immediately after collection and then immediately stored at -80\u0026deg;C. Plasma concentrations of IL-6, IL-8, and IL-10 were determined using enzyme-linked immunosorbent assay (ELISA) according to manufacturers\u0026rsquo; instructions (MultiSciences Biotech Co., Ltd., Hangzhou, Zhejiang, China). Plasma levels of CRP were determined using an immuno-scatter turbidmetry (Lifotronic Technology Co., Ltd., Shenzhen, China). Leukaemia cell lines were determined using a five-classification haematology analyser (Sysmex Corporation, Shanghai, China).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSample size calculation\u003c/h2\u003e \u003cp\u003eThe sample size was calculated based on a previous study\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e in which researchers compared the concentration of IL-6 the patients under esketamine-based anaesthesia with that of those under sufentanil-based anaesthesia. The sample size was calculated, with a mean of 56.75 and a standard deviation of 46.28 in the esketamine group and a mean of 172.64 and a standard deviation of 149.93 in the sufentanil group; the mean difference was 115.89, with a power of 80%, and an alpha error of 5%. The sample size calculated was at least 15, and we added 3 subjects considering a nonparticipation rate of 20%. The final sample size was at least 18 in each group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using SPSS Statistics Version 26.0. Data were summarized using the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation in quantitative data and numbers (percentages) for categorical data. Repeated measures ANOVA was used for the comparison of serial measurements within a single group. Data from the two groups were analysed using the paired Student\u0026rsquo;s t test or Wilcoxon test for quantitative data and the chi-square test for qualitative data.\u003c/p\u003e \u003cp\u003ep values below 0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv class=\"Section2\" id=\"Sec11\"\u003e\n \u003ch2\u003ePatient and perioperative characteristics\u003c/h2\u003e\n \u003cp\u003eA total of 50 patients with wedge resections as well as total lobectomies were enrolled in the study: 22 in the sufentanil group and 22 in the esketamine group (Fig. 1). None of these patients had any signs of preoperative pulmonary or systemic infection. There was no difference regarding biometric data, surgical procedures, duration of surgery, OLV and mechanical ventilation (MV), or length of hospital stay between the two groups, however the esketamine group had less blood loss (11.14\u0026thinsp;\u0026plusmn;\u0026thinsp;4.86 ml) than the sufentanil group (28.18\u0026thinsp;\u0026plusmn;\u0026thinsp;18.16 ml) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\"\u003eTable 1 Patient and perioperative characteristics\u003c/div\u003e\n \u003ctable border=\"1\" id=\"Taba\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSufentanil\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEsketamine\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eBiometric Data\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58.77\u0026thinsp;\u0026plusmn;\u0026thinsp;11.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58.55\u0026thinsp;\u0026plusmn;\u0026thinsp;8.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.943\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17(77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14(64%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.322\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeight, kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61.77\u0026thinsp;\u0026plusmn;\u0026thinsp;8.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61.68\u0026thinsp;\u0026plusmn;\u0026thinsp;9.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.878\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHeight, cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e163.41\u0026thinsp;\u0026plusmn;\u0026thinsp;5.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e164.23\u0026thinsp;\u0026plusmn;\u0026thinsp;10.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.743\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI, kg/m2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.15\u0026thinsp;\u0026plusmn;\u0026thinsp;3.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.85\u0026thinsp;\u0026plusmn;\u0026thinsp;2.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.737\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18(82%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16(73%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.472\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eASA class I/II/III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1/19/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0/21/1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.488\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003ePerioperative Data\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProcedures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.131\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePulmonary Lobectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9(41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14(64%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWedge-shaped excision of lung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13(59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8(36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDuration of OLV, min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e79.59\u0026thinsp;\u0026plusmn;\u0026thinsp;38.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65.14\u0026thinsp;\u0026plusmn;\u0026thinsp;27.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.162\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDuration of MV, min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e121.55\u0026thinsp;\u0026plusmn;\u0026thinsp;40.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e103.27\u0026thinsp;\u0026plusmn;\u0026thinsp;30.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDuration of Surgery, min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e98.77\u0026thinsp;\u0026plusmn;\u0026thinsp;33.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82.45\u0026thinsp;\u0026plusmn;\u0026thinsp;29.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.107\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlood loss, ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.18\u0026thinsp;\u0026plusmn;\u0026thinsp;18.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.14\u0026thinsp;\u0026plusmn;\u0026thinsp;4.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.000\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLength of hospital stay, days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.82\u0026thinsp;\u0026plusmn;\u0026thinsp;3.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.77\u0026thinsp;\u0026plusmn;\u0026thinsp;2.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.374\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eData are expressed as absolute numbers in mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or number(percentage).\u003c/p\u003e\n \u003cp\u003eBMI\u0026thinsp;=\u0026thinsp;Body Mass Index, ASA\u0026thinsp;=\u0026thinsp;American Society of Anesthesiologists, OLV\u0026thinsp;=\u0026thinsp;one-lung-ventilation, MV\u0026thinsp;=\u0026thinsp;mechanical ventilation\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e*\u003c/sup\u003e: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 vs the Sufentanil group.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec12\"\u003e\n \u003ch2\u003eInflammatory response after OLV\u003c/h2\u003e\n \u003cp\u003eOLV resulted in an increase in the IL-6 and IL-10 plasma levels in both the sufentanil and the esketamine groups (Figs.\u0026nbsp;2 and 4). It is worth noting that the concentrations of IL-8 increased in the sufentanil group but decreased significantly in the esketamine group (Fig.\u0026nbsp;3). No statistically significant difference was detected in the concentration of IL-6, IL-8, or IL-10 between the two groups of patients before anaesthesia induction and 1 h after OLV. However, we observed a significantly diminished postoperative increase in the proinflammatory cytokines, IL-6 (P\u0026thinsp;=\u0026thinsp;0.029) and IL-8 (P\u0026thinsp;=\u0026thinsp;0.026), in the esketamine group when compared with the sufentanil group (Figs.\u0026nbsp;2 and 3) 2 h after the intrathoracic procedure. In addition, patients in the esketamine group showed a higher level of the anti-inflammatory cytokine IL-10 (P\u0026thinsp;=\u0026thinsp;0.223) 2 h after the intrathoracic procedure, but the difference was not statistically significant (Fig.\u0026nbsp;4).\u003c/p\u003e\n \u003cp\u003eBlood differential leukocyte count and CRP were assessed preoperatively and postoperatively as additional markers for inflammation. There was no statistically significant difference in CRP or leukocytes between the anaesthesia groups preoperatively (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Postoperative levels of CRP and differential leukocyte count were significantly higher in the two groups when compared with preoperative levels (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), except for the level of lymphocyte count, which was significantly lower postoperatively (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). It is worth noting that CRP, a highly sensitive marker of the acute system response, was significantly lower in the esketamine group than in the sufentanil group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig. 5).\u0026nbsp;\u003c/p\u003e\n \u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eInflammatory cells\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSufentanil\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEsketamine\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eWBC(*10\u003csup\u003e^\u003c/sup\u003e9/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePre-op\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.85\u0026thinsp;\u0026plusmn;\u0026thinsp;1.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.49\u0026thinsp;\u0026plusmn;\u0026thinsp;1.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.312\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePost-op\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.60\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.08\u0026thinsp;\u0026plusmn;\u0026thinsp;3.04\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.541\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eMONO(*10\u003csup\u003e^\u003c/sup\u003e9/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePre-op\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.41\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePost-op\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.83\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.85\u0026thinsp;\u0026plusmn;\u0026thinsp;0.36\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.681\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eLY(*10\u003csup\u003e^\u003c/sup\u003e9/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePre-op\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePost-op\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.40\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.285\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eNEUT(*10\u003csup\u003e^\u003c/sup\u003e9/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePre-op\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePost-op\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10.64\u0026thinsp;\u0026plusmn;\u0026thinsp;2.65\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10.20\u0026thinsp;\u0026plusmn;\u0026thinsp;2.76\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.681\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eCRP (mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePre-op\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.88\u0026thinsp;\u0026plusmn;\u0026thinsp;1.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.75\u0026thinsp;\u0026plusmn;\u0026thinsp;2.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.858\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePost-op\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e49.71\u0026thinsp;\u0026plusmn;\u0026thinsp;29.60\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24.36\u0026thinsp;\u0026plusmn;\u0026thinsp;12.64\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eWBC\u0026thinsp;=\u0026thinsp;white blood cell count, MONO\u0026thinsp;=\u0026thinsp;monocyte count, LY\u0026thinsp;=\u0026thinsp;lymphocyte count, NEUT\u0026thinsp;=\u0026thinsp;neutrophil count, CRP\u0026thinsp;=\u0026thinsp;C-reaction protein, Pre-op\u0026thinsp;=\u0026thinsp;preoperation, Post-op\u0026thinsp;=\u0026thinsp;postoperation\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003e* Differences within the single study group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). \u003csup\u003e#\u003c/sup\u003e Differences between the sufentanil and esketamine anaesthesia patient\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe main finding of the study is that esketamine used as the sole analgesic during thoracic surgery reduces the release of the proinflammatory cytokine associated with OLV. Furthermore, compared with sufentanil-based anaesthesia, esketamine may also be able to alleviate the systemic inflammatory response postoperatively, as was suggested by the lower level of CRP 24 hours after surgery.\u003c/p\u003e \u003cp\u003eThoracic surgery, including oesophagectomy and lobectomy, induces a more severe systemic inflammatory reaction than other routine surgeries\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. This is most likely due to the use of OLV during thoracic procedures. Mechanical ventilation itself may induce pulmonary damage due to high inspiratory pressure and shear forces following the opening and collapse of alveoli\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Ventilation-induced injury is further amplified by the OLV strategy, which collapses the surgically treated lung and delivers the whole tidal volume to the other lung\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Surgical manipulation, lung collapse and re-expansion\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e, high oxygen tension\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e, and capillary shear stress because of hyperperfusion\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e or high tidal volumes and increased airway pressures\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e during OLV may cause further pulmonary damage, thus inducing systemic proinflammatory responses. In addition, during the OLV period, the collapsed lung is in a state of hypoxia, and subsequently, hypoxic pulmonary vasoconstriction (HPV) occurs. Therefore, another possible reason lung injury induced by OLV is vascular endothelial damage following reperfusion injury in areas of prior hypoxic constriction, with the resulting reactive oxygen species disrupting the permeability of the vascular endothelium.\u003c/p\u003e \u003cp\u003eVentilation-induced pulmonary injury is characterized by alveolar wall disruption, immune cell recruitment, inflammatory cytokine production, excessive reactive oxygen species production, and oedema formation \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. First, inflammatory cells such as lymphocytes, macrophages, and neutrophils produce cytokines in an autocrine way, and then the alveolar epithelial cells, fibroblast cells, and endothelial cells produce more cytokines in a paracrine manner, forming a \u0026ldquo;waterfall\u0026rdquo; effect. Although the initial step of this process is limiting inflammation locally to alleviate pulmonary symptoms, this response can progress to systemic inflammation. The excessive secretion of proinflammatory cytokines is detrimental to the proper functioning of the organism, leading to a loss of organ function and potential multiorgan failure. Appropriate inhibition of the inflammatory response is conducive to the recovery of patients, thus reducing the occurrence of complications, which is also a requirement for fast-track surgery. The normal concentration of these cytokines is necessary for the physiological function of the immune system.\u003c/p\u003e \u003cp\u003eHowever, an intuitive way to detect cytokine changes during lung injury is to examine them in bronchoalveolar lavage (BAL) fluid. However, Douzinas et al. found that the levels of IL-1β and IL-6 in the arterial blood of acute respiratory distress syndrome (ARDS) patients increased, suggesting that the lung injury of these patients was involved in the release of cytokines into the systemic circulation\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Moreover, they pointed out that the concentration of cytokines in arterial blood was higher than that in venous blood and was closer to those in the lung. In addition, interindividual differences were apparent in the alveolar lavage fluid but less so in blood. Therefore, in this study, we were inclined to determine the concentrations of IL-6, IL-8, and IL-10 in the arterial blood of patients to indicate the degree of OLV-induced lung injury, which is more practical in clinical research.\u003c/p\u003e \u003cp\u003eSeveral experimental and clinical studies have shown that the selection of anaesthetic agents may have an impact on the immune system. Some anaesthetic protocols may be involved in immunosuppressive effects. Ketamine, a noncompetitive NMDA receptor antagonist, is known to produce increases in blood pressure and stroke volume, which enables it to be broadly applied in clinical practice. It has also been shown to possess anti-inflammatory effects, probably related to inflammatory cell recruitment, the regulation of inflammatory mediators, and the secretion of inflammatory cytokines. In vitro and in vivo data from several studies indicate that ketamine suppresses the function of lymphocytes, neutrophils, and natural killer cells \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Furthermore, Weigand et al. demonstrated that racemic ketamine and its isomers esketamine and R(-)ketamine have comparable inhibitory effects, implying that the suppression of irritated neutrophil function is probably not mediated by receptor-specific interactions\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Wu et al. proposed that ketamine decreased tumour necrosis factor (TNF)-α and IL-6 biosynthesis in lipopolysaccharide-activated macrophages through inhibition of activator protein-1 translocation and Toll-like receptor 4-dependent Jun N-terminal kinase activation \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Furthermore, Chen et al. found that ketamine remarkably prohibits lipopolysaccharide-induced nuclear factor-κB (NF-κB) translocation and transcriptional activation, thereby diminishing the production of TNF-α, IL-1β and IL-6\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Thus, there is accumulating evidence that ketamine can inhibit signalling pathways and transcription factors for proinflammatory cytokines to reduce the release of these cytokines. However, the anti-inflammatory mechanism of esketamine remains uncertain and requires extensive experimental evidence.\u003c/p\u003e \u003cp\u003eA key finding from our studies is that, compared with sufentanil-based analgesia, esketamine as the sole analgesic is better at alleviating IL-6 and IL-8 release at 2 h after the intrathoracic procedure, when the release of inflammatory cytokines is higher than other times in patients undergoing thoracic surgery with OLV\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. In a study of patients undergoing coronary artery bypass grafting with extracorporeal circulation, the patients in whom anaesthesia was induced and maintained with esketamine had significantly lower increases in the proinflammatory cytokines IL-6 and IL-8 6 h after the opening of the aorta than those in the sufentanil group, while the anti-inflammatory cytokine IL-10 showed higher levels in the esketamine group, thus suggesting that esketamine has similar anti-inflammatory properties\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. A recent study has shown that subanesthetic esketamine administered at the induction of anaesthesia was more conducive in relieving the inflammatory response in elderly surgical patients based on its lower increase in CRP, procalcitonin, and the white blood cell count in blood than sufentanil\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. However, in this study, esketamine was used as an adjunct to sufentanil-based anaesthesia. All these studies suggest that esketamine has beneficial effects on the immune response in the perioperative period of different procedures, which is consistent with our findings. Of note, Wang et al. also reported that the administration of low-dose ketamine to patients with acute lung injury resulting from mechanical ventilation could significantly decrease inflammatory factors such as IL-1β, Caspase-1, and NF-κB \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. In addition to the anti-inflammatory effects mentioned above, this study also indicated that ketamine could improve the pulmonary ventilation and gas exchange function of patients, shorten the time of the ventilation, improve the success rate of deconditioning, and reduce the mortality rate. Not only does this illustrate the benefit of ketamine in alleviating the inflammatory response in patients with lung injury, it also provides additional evidence that its use in patients with lung injury has a facilitative role in their recovery.\u003c/p\u003e \u003cp\u003eIncreased expression of proinflammatory cytokines, especially IL-6 and IL-8, after lung resection is associated with increases in the incidence of postoperative complications (atelectasis, pneumonia, pleural empyema, atrial fibrillation, etc.)\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e and the systemic inflammatory response, which are predictors of length of hospital stay\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. IL-6 is a modulator of the immune response, acute-phase response, and haematopoiesis produced by lymphocytes or nongonadal cells. Sparrow et al. noted that the suppression of systemic IL-6 significantly mitigated neuronal injury in the frontal cortex and hippocampus in mice after MV\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e, suggesting that in addition to lung injury and pulmonary complications, IL-6 is related to ventilator-induced neuronal injury. This would further indicate that the reduction in IL-6 levels in our findings is of significant importance and provides strong support for the clinical use of esketamine during OLV. IL-8 is considered a specific cytokine of the pulmonary inflammatory response and tissue injury, which can reflect the degree of lung injury. The concentration of IL-8 was found to be significantly elevated in the BAL fluid of ARDS patients, and patients with high IL-8 concentrations in the BAL fluid had higher death rates than those with lower concentrations \u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. It should be noted that the concentrations of IL-8 were elevated in the sufentanil group and decreased in the esketamine group in our study. Several clinical studies have shown that mechanical ventilation induces an increase in IL-8 in both the lungs and the circulatory system\u003csup\u003e[\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. Nevertheless, we found a significant decrease in IL-8 levels in the esketamine group, suggesting that esketamine-based anaesthesia has an efficient effect on decreasing IL-8 release during thoracic surgery. Therefore, based on our findings, we suggest that the administration of esketamine for anaesthesia has potential anti-inflammatory effects, which are beneficial for reducing the incidence of postoperative pulmonary complications and alleviating perioperative lung injury induced by surgery and mechanical ventilation in patients under OLV during surgery.\u003c/p\u003e \u003cp\u003eHowever, in our study, although patients in the esketamine group had a higher concentration of postoperative IL-10 than those in the sufentanil group, the result was not statistically significant. IL-10 is a cytokine with a promising anti-inflammatory effect that not only directly inhibits the inflammatory response itself but also alleviates the tissue damage triggered by inflammation. An endotoxin study in a rat model of acute lung injury discovered that exogenous IL-10 can attenuate lung injury by reducing proinflammatory cytokines in pulmonary tissue \u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. Chen et al. investigated whether IL-10 alleviates mechanical ventilation-induced pulmonary injury through two major routes: the oxidative stress pathway and the inflammatory response pathway \u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. However, in our study, we found no effect of ketamine on IL-10. Further detailed studies are therefore needed to identify the primary effect of esketamine on the production of IL-10 during thoracic surgery.\u003c/p\u003e \u003cp\u003eMoreover, we have also found that esketamine has the potential to alleviate the postoperative systemic inflammatory response, as was suggested by the lower level of CRP 24 hours after surgery compared with sufentanil-based anaesthesia. CRP is a general indicator of inflammation created by the liver as a response to cytokines involved in physical stress, necrosis, or infection. The higher the perioperative CRP level, the worse the prognosis, regardless of whether serious postoperative complications develop. CRP is a particularly sensitive but nonspecific sign of the acute phase response\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. Okada et al. prospectively analysed 356 patients who underwent lobectomy and identified significantly poorer overall survival and recurrence-free survival in patients with higher perioperative CRP \u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. Similarly, Hara et al. revealed that patients with lower postoperative CRP levels undergoing radical surgery for non-small cell lung cancer had significantly higher 5-year disease recurrence, survival and overall survival rates than those with higher levels \u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. Based on this finding, we suggest that the use of ketamine in thoracic surgery may reduce the acute postoperative inflammatory response and thus reduce the risk of postoperative mortality.\u003c/p\u003e \u003cp\u003eIn addition to the anti-inflammatory effect, a significant reduction in blood loss was observed in the esketamine group. Intraoperative blood loss is usually due to the oozing of blood from the wound vein, and arterial bleeding is usually\u003c/p\u003e \u003cp\u003eobvious and quickly stopped \u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. We believe that the reduction in blood loss observed in our study may be related to the more stable haemodynamics resulting from esketamine anaesthesia. Unfortunately, intraoperative haemodynamics were not recorded in our study. However, in another study, Li et al. found that low-dose esketamine for anaesthesia in elderly patients undergoing knee arthroplasty may better maintain the stability of haemodynamics\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. Reduced bleeding decreases the need for allogeneic blood transfusions and autologous blood transfusions, resulting in faster postoperative recovery and fewer complications\u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e. Therefore, the use of esketamine for anaesthesia can not only alleviate the postoperative inflammatory response but also reduce intraoperative blood loss and further reduce the risk of perioperative complications of patients.\u003c/p\u003e \u003cp\u003eSeveral limitations of this study were noted. First, the study was performed at a single centre, indicating that the results are reflective of clinical practice at the authors' institution and are not generalizable. Second, this strategy permits the use of other intravenous anaesthetics (e.g., dexmedetomidine and midazolam) and inhaled anaesthetics (sevoflurane), which is similar to actual clinical practice, and outcomes can be impacted by these drugs. Although the administration of other anaesthetic agents was similar in the two groups, the authors could not rule out the effect of the interaction of the drugs. Moreover, the most noteworthy limitation of this study is the short-term postoperative observational period. The long-term effects of intraoperative anaesthetic drugs remain to be elucidated.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, our results demonstrate that OLV induces the production and release of inflammatory cytokines into the bloodstream in patients undergoing thoracic surgery. The administration of esketamine, as a sole analgesic, suppresses the systemic inflammatory response in patients undergoing thoracic surgery with OLV and alleviates the effects on serum IL-6 and IL-8 expression. Thus, esketamine has a prospective impact on reducing inflammation related to OLV and intraoperative blood loss in patients undergoing thoracic surgery. Esketamine in thoracic surgery appears to be more beneficial than opioids. Further studies are needed to demonstrate the anti-inflammatory and other advantages of esketamine application in patients undergoing thoracic surgery under OLV.\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\"\u003eVATS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003evideo-assisted thoracic surgery\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eC-reactive protein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNMDA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eN-methyl-D-aspartate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSpO\u003csub\u003e2\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoxygen saturation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFIO\u003csub\u003e2\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einspired oxygen\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePaCO\u003csub\u003e2\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epartial pressure of carbon dioxide\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\"\u003eMV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emechanical ventilation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHPV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehypoxic pulmonary vasoconstriction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBAL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebronchoalveolar lavage\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eARDS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eacute respiratory distress syndrome\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\"\u003eNF-κB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enuclear factor-κB.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Institutional Review Board of Shanghai Changzheng Hospital on March 30, 2022, under the reference 2022SL033 and carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. Written informed consent was obtained from all patients. The trial was retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR2200065915, date of registration: 2022-11-18).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors received no funding for this work.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors\u0026rsquo; contributions\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript. Song WX helped supervise the data collection, analyze the data, prepared, drafted, and reviewed the manuscript; Huang XS helped supervise the data collection, reviewed the literature, and provided surgical content expertise; Li YK helped provided anaesthesiology content expertise, supervised the data collection analyzed the data, edited the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgment\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSugasawa Y, Yamaguchi K, Kumakura S, Murakami T, Kugimiya T, Suzuki K, Nagaoka I, Inada E: \u003cstrong\u003eThe effect of one-lung ventilation upon pulmonary inflammatory responses during lung resection\u003c/strong\u003e. \u003cem\u003eJ Anesth\u0026nbsp;\u003c/em\u003e2011, \u003cstrong\u003e25\u003c/strong\u003e(2):170-177.\u003c/li\u003e\n \u003cli\u003eLohser J, Slinger P: 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Surg\u0026nbsp;\u003c/em\u003e2010, \u003cstrong\u003e16\u003c/strong\u003e(2):85-90.\u003c/li\u003e\n \u003cli\u003eDavies MJ: \u003cstrong\u003eMinimising intra-operative blood loss\u003c/strong\u003e. \u003cem\u003eTransfus Apher Sci\u0026nbsp;\u003c/em\u003e2002, \u003cstrong\u003e27\u003c/strong\u003e(1):55-57.\u003c/li\u003e\n \u003cli\u003eLi J, Wang Z, Wang A, Wang Z: \u003cstrong\u003eClinical effects of low-dose esketamine for anaesthesia induction in the elderly: A randomized controlled trial\u003c/strong\u003e. \u003cem\u003eJ Clin Pharm Ther\u0026nbsp;\u003c/em\u003e2022, \u003cstrong\u003e47\u003c/strong\u003e(6):759-766.\u003c/li\u003e\n \u003cli\u003eMatsuura N, Okamura T, Ide S, Ichinohe T: \u003cstrong\u003eRemifentanil Reduces Blood Loss During Orthognathic Surgery\u003c/strong\u003e. \u003cem\u003eAnesth Prog\u0026nbsp;\u003c/em\u003e2017, \u003cstrong\u003e64\u003c/strong\u003e(1):3-7.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"anaesthetics, esketamine, one-lung ventilation, immune response, thoracic surgery, lung protection","lastPublishedDoi":"10.21203/rs.3.rs-2254255/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2254255/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThoracic surgery with one-lung ventilation (OLV) leads to a postoperative inflammatory response. In this prospective randomized study, we compared the effect of esketamine-based anaesthesia on perioperative inflammatory cytokine levels in patients under routine anaesthesia with opioids undergoing thoracic surgery with OLV.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eAdult patients undergoing wedge resections or total lobectomies under video-assisted thoracic surgery (VATS) were randomly assigned (1:1) to receive esketamine-based anaesthesia (Esketamine group, n\u0026thinsp;=\u0026thinsp;22) or sufentanil-based anaesthesia (Sufentanil group, n\u0026thinsp;=\u0026thinsp;22). Blood samples for measurement of inflammatory factors were collected from the radial artery at three time points: before anaesthesia induction (T1); 1 h after OLV (T2) and 2 h after surgery (T3). Peripheral venous blood was collected 24 hours before surgery (Preop) and 24 hours after surgery (Postop) to measure leukaemia cell lines and C-reactive protein (CRP).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eCompared with the sufentanil group, the increase in proinflammatory cytokines interleukin (IL)-6 (10.23\u0026thinsp;\u0026plusmn;\u0026thinsp;5.60 vs. 20.97\u0026thinsp;\u0026plusmn;\u0026thinsp;18.22 pg/ml, P\u0026thinsp;=\u0026thinsp;0.029) and IL-8 secretions (4.88\u0026thinsp;\u0026plusmn;\u0026thinsp;18.29 vs. 81.69\u0026thinsp;\u0026plusmn;\u0026thinsp;130.34 pg/ml, P\u0026thinsp;=\u0026thinsp;0.026) was significantly lower in the esketamine group 2 h after the intrathoracic procedure. CRP levels (24.36\u0026thinsp;\u0026plusmn;\u0026thinsp;12.64 vs. 49.71\u0026thinsp;\u0026plusmn;\u0026thinsp;29.60 mg/L, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and blood loss volumes (11.14\u0026thinsp;\u0026plusmn;\u0026thinsp;4.86 ml vs. 28.18\u0026thinsp;\u0026plusmn;\u0026thinsp;18.16 ml, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were significantly lower in the esketamine group than in the sufentanil group (24.36\u0026thinsp;\u0026plusmn;\u0026thinsp;12.64 vs. 49.71\u0026thinsp;\u0026plusmn;\u0026thinsp;29.60, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). There was no difference in biometric data, surgical procedures, duration of surgery, OLV and mechanical ventilation, or length of hospital stay among the groups.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur study demonstrates that esketamine possesses potent anti-inflammatory properties. Anaesthesia with esketamine may play a beneficial role in reducing both the OLV-induced systemic inflammatory response and intraoperative blood loss.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e \u003cp\u003eChiCTR2200065915. Registered on 18/11/2022.\u003c/p\u003e","manuscriptTitle":"Effects of esketamine-based anaesthesia on the Systemic Inflammatory Response in Thoracic Surgical Patients: a prospective, single-center, randomized, controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-12-01 18:56:36","doi":"10.21203/rs.3.rs-2254255/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9c88c05a-10b1-4864-a3e3-8ce7d050e119","owner":[],"postedDate":"December 1st, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-02-16T20:29:29+00:00","versionOfRecord":[],"versionCreatedAt":"2022-12-01 18:56:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2254255","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2254255","identity":"rs-2254255","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}