DOI: https://doi.org/10.21203/rs.3.rs-2254255/v1
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.
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).
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.
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.
ChiCTR2200065915. Registered on 18/11/2022.
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.
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.
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/m2, 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 (SpO2) 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.
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.
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 cmH2O. The positive end-expiratory pressure was set to 4 ~ 5 cmH2O. The fraction of inspired oxygen (FIO2) was set at 0.5 ~ 0.7 after induction and adjusted to 0.8 ~ 1.0 when patients were placed under OLV to maintain SpO2 > 90%. The tidal volume was set to 6 ml/kg, and the respiratory rate was adjusted to maintain partial pressure of carbon dioxide (PaCO2) between 35 and 45 mmHg. We inflated the collapsed lung periodically.
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.
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).
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 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.
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).
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.
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).
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 |
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.
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.
one-lung ventilation
video-assisted thoracic surgery
C-reactive protein
N-methyl-D-aspartate
oxygen saturation
inspired oxygen
partial pressure of carbon dioxide
interleukin
mechanical ventilation
hypoxic pulmonary vasoconstriction
bronchoalveolar lavage
acute respiratory distress syndrome
tumor necrosis factor
nuclear factor-κB.
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.