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.