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

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.

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.

Results

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

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

1. 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.
2. 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.
3. 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. Cytokine 1994, 6(2):181-186.
4. Kaufmann KB, Heinrich S, Staehle HF, Bogatyreva L, Buerkle H, Goebel U: Perioperative cytokine profile during lung surgery predicts patients at risk for postoperative complications-A prospective, clinical study. PLoS One 2018, 13(7):e0199807.
5. Alhayyan A, McSorley S, Roxburgh C, Kearns R, Horgan P, McMillan D: The effect of anaesthesia on the postoperative systemic inflammatory response in patients undergoing surgery: A systematic review and meta-analysis. Surg Open Sci 2020, 2(1):1-21.
6. Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, Pereira EFR, Albuquerque EX, Thomas CJ, Zarate CA, Jr. et al: Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacol Rev 2018, 70(3):621-660.
7. Liu FL, Chen TL, Chen RM: Mechanisms of ketamine-induced immunosuppression. Acta Anaesthesiol Taiwan 2012, 50(4):172-177.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. Sugita J, Fujiu K: Systemic Inflammatory Stress Response During Cardiac Surgery. Int Heart J 2018, 59(3):457-459.
24. 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.
25. Allen TC, Kurdowska A: Interleukin 8 and acute lung injury. Arch Pathol Lab Med 2014, 138(2):266-269.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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.
33. 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.
34. Davies MJ: Minimising intra-operative blood loss. Transfus Apher Sci 2002, 27(1):55-57.
35. 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.
36. Matsuura N, Okamura T, Ide S, Ichinohe T: Remifentanil Reduces Blood Loss During Orthognathic Surgery. Anesth Prog 2017, 64(1):3-7.