Lung-protective effects of esketamine in patients undergoing video-assisted thoracoscopic surgery: a randomized controlled trial

Introduction

After the coronavirus disease 2019 (COVID-19) pandemic, the clinical detection rate of lung cancer markedly increased. Among malignancies, lung cancer is the second most common, with 2 million new diagnoses and 1.8 million related deaths each year (1). Video-assisted thoracoscopic surgery (VATS), as the recommended treatment for patients with early-stage non-small lung cancer, is associated with a low complication rate, high 5-year survival rate, short intercostal drainage duration, and reduced postoperative pain as compared to conventional thoracotomy (2,3). Lung-protective ventilation strategies, preoperative respiratory function exercises, multimodel analgesia, and the application of certain anesthetics are commonly adopted by anesthetists to prevent the occurrence of lung injury in patients undergoing VATS (4-7). However, due to the hyperperfusion and ventilator-induced injury of the nonoperative lung, ischemia-reperfusion injury and shear stress on reventilation of the collapsed lung, and elevated levels of inflammatory cytokines or reactive oxygen species due to surgical manipulation, the incidence of lung injury remains high (8,9). Acute lung injury caused by these physiological mechanisms is the main factor hindering the rapid recovery after surgery and is also closely associated with increased postoperative pulmonary complications (PPCs) and mortality.

Esketamine, a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, is the S-enantiomer of ketamine; compared to ketamine, it has stronger sedative and analgesic effects, fewer adverse events, and less cardiorespiratory depression (10). Esketamine was approved by the US Food and Drug Administration (FDA) in 2019 and is now widely used in anesthesia induction and maintenance, acute and chronic pain management, antidepressant treatment, and critical care medicine (11,12). Studies have examined the application of esketamine in pediatric surgery, outpatient gastrointestinal endoscopy, obstetric anesthesia, and postoperative assisted analgesia and evaluated its ability to reduce opioid consumption and opioid-induced cough, prolong the duration of analgesic action, and decrease induction hypotension through its sympathetic stimulation and antagonism of the NMDA receptor (13-16). One study demonstrated that the use of ketamine can result in a lower pain score, higher postoperative percutaneous pulse oxygen saturation (SpO₂), and greater anti-inflammatory effect after thoracic surgery due to its remarkably stable hemodynamic properties, desirable respiratory parameters, and effective counteraction of opioid-induced respiratory depression (17-20). Esketamine may theoretically aid in improving patients’ postoperative prognosis, yet research on whether esketamine can improve lung function and on the related dose-effect relationship is lacking.

Thus, we conducted a study to determine whether intravenous administration of esketamine can improve pulmonary function, clarify the underlying mechanisms of its action, and examine the influence of dosage on the lung-protective effect in patients undergoing VATS. We present this article in accordance with the CONSORT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-999/rc).

Methods

Design and patients

This randomized controlled trial was registered in the Chinese Clinical Trials Registry (registration No. ChiCTR2100051518; date: September 25, 2021). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of The First Affiliated Hospital of Chongqing Medical University (approval No. 2021-318). Informed consent was obtained from all individual participants.

Patients were recruited between September 2021 and June 2022 at the Department of Thoracic Surgery, The First Affiliated Hospital of Chongqing Medical University. Patients with an American Society of Anesthesiologists (ASA) physical status classification of II–III, an age of 18–65 years, and a body mass index (BMI) between 18 and 30 kg/m² and who were scheduled for elective VATS were screened for enrollment. The exclusion criteria were contraindications to esketamine, poorly unregulated or malignant hypertension (systolic/diastolic blood pressure over 180/110 mmHg), untreated or undertreated hyperthyroidism, severe cardiopulmonary or liver or kidney dysfunction, mental illness or substance abuse, an inability to understand study, refusal to participate, and a persistently intraoperative SpO₂ <90% even after adjustment via fiberoptic bronchoscopy.

Randomization

Before initiation of the study, all enrolled participants were randomized into three groups in a 1:1:1 ratio through a sequence of computer-generated randomized numbers: the low-dose esketamine group (group K1), high-dose esketamine group (group K2), or control group (group C). For allocation concealment, the group assignment and drug preparation instruction were placed inside sequentially numbered, sealed envelopes. An independent research assistant was responsible for opening the envelopes and drug preparation and had no additional involvement in the study. All those involved in the study, including enrolled patients, surgeons, and the follow-up personnel, were kept blind to the drug and the group assignments. Group K1 received 0.5 mg/kg of esketamine diluted with normal saline to 20 mL via intravenous injection before induction, which was followed by a maintenance infusion of 20 mL/h (0.5 mg/kg of esketamine diluted with normal saline to 20 mL) during surgery; group K2 received 1.0 mg/kg of esketamine diluted with normal saline to 20 mL via intravenous injection before induction, which was followed by a maintenance infusion of 20 mL/h (0.5 mg/kg of esketamine diluted with normal saline to 20 mL) during surgery; and group C received an equal volume of normal saline injection and continuous intravenous infusion.

All patients received routine preoperative preparation, with monitoring of electrocardiography (ECG), SpO₂, invasive blood pressure (IBP), and the bispectral index (BIS). Intravenous general anesthesia was induced with midazolam (0.02–0.04 mg/kg), propofol (1.5–2 mg/kg), sufentanil (0.4–0.5 µg/kg), and vecuronium bromide (0.1 mg/kg). Lung isolation ventilation was performed via a double-lumen tracheal tube, and anesthesia was maintained with continuous intravenous infusion of propofol (4–8 mg/kg/h) and remifentanil (9–18 µg/kg/h), with intermittent injections of vecuronium bromide. The dosage of medications was adjusted to maintain a BIS value between 40 and 60. All patients received the same ventilation strategy. Two-lung ventilation was conducted with the following parameters: tidal volume (Vt), 6–8 mL/kg; fraction of inspired oxygen (FiO₂) after induction of anesthesia, 100%; FiO₂ restoration of two-lung ventilation, 50%; respiratory rate, 10–12/min; and inspiratory-to-expiratory ratio, 1:2. Meanwhile, one-lung ventilation (OLV) was conducted with the following parameters: Vt, 4–6 mL/kg; inhaled oxygen concentration, 100%; respiratory rate, 14–16/min, positive end-expiratory pressure (PEEP), 5 cmH₂O; and inspiratory-to-expiratory ratio, 1:2. The end-expiratory carbon dioxide partial pressure (ETCO₂) was maintained between 35 and 45 mmHg. At the end of surgery, all patients were changed to single-lumen endotracheal tubes and transferred to the intensive care unit (ICU) of the Department of Thoracic Surgery. All patients received the same postoperative analgesic regimen, in which the thoracic surgeon placed an analgesic pump subcutaneously.

Measurements

Radial arterial blood collected before induction of anesthesia (T0), after intubation (T1), 30 minutes after OLV (T2), 1 hour after OLV (T3), 15 minutes after the resumption of two-lung ventilation (T4), admission to the ICU (T5), after extubation (T6), discharge from the ICU (T7), and 24 hours postoperatively (T8). Venous blood was collected 24 hours postoperatively to determine the white blood cell count, neutrophil percentage, and procalcitonin level.

Blood pressure and heart rate were recorded from T0 to T4, and respiratory parameters, including Vt, end-tidal carbon dioxide partial pressure (PetCO₂), dynamic lung compliance (Cdyn), static lung compliance (Cst), and dead space fraction (Vd/Vt), were recorded from T1 to T4 during mechanical ventilation. The arterial-alveolar oxygen partial pressure ratio (a/A ratio), oxygenation index (OI), alveolar-arterial partial pressure difference of oxygen (A-aDO₂), and respiratory index (RI) from T0 to T8 were calculated through arterial blood gas analysis via the following calculation formulae:

• $PA{O}_2=Fi{O}_2\times \left(atmosphericpressure-H_{2}Opressure\right)-1.25\times PaC{O}_2$
• $a/A=Pa{O}_2/PA{O}_2$
• $OI=Pa{O}_2/Fi{O}_2$
• $RI=A\text{-}aD{O}_2/Pa{O}_2$
• $\begin{array}{l}A\text{-}aD{O}_2=P_A{O}_2-Pa{O}_2\\ \text{}=713Fi{O}_2-PaC{O}_2/0.8-Pa{O}_2\end{array}$
• $Cdyn=Vt/\left(peakinspiratorypressure-PEEP\right)$
• $Cst=Vt/\left(plateaupressure-PEEP\right)$
• $Vd/Vt=\left(PaC{O}_2-PetC{O}_2\right)/PaC{O}_2$

Primary and secondary outcomes

In our study, the primary outcome was the a/A ratio. The secondary outcomes included the following: (I) other variables reflecting pulmonary function (OI, A-aDO₂, RI, Cdyn, Cst, and Vd/Vt); (II) the ICU and hospital length of stays; (III) the dosage of anesthetics (propofol, sufentanil, and remifentanil); (IV) the incidence of postoperative nausea and vomiting or other adverse effects; (V) the incidence of PPCs 7 days after surgery; and (VI) the 11-point numerical rating scale (NRS) score for pain (with 0 indicating no pain and 10 indicating the most severe pain) at 24 hours postoperatively and 48 hours during rest and movement, respectively.

Statistical analysis

Sample size calculation was performed via PASS 15.0 software (NCSS LLC, Kaysville, UT, USA). Based on our preliminary trial involving 20 patients who underwent VATS, the a/A ratio at 24 hours postoperatively, reflecting the lung gas exchange function, was 65.7±17.5 in group C and 78.2±18.3 in group K1. With the power set to 0.9 and α to 0.05, 45 patients were deemed to be required in each group. Assuming a dropout rate of 20%, we planned to have 57 patients in each group, for a total of 171 patients.

SPSS version 26.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. The measurement variables with a normal distribution are expressed as the mean ± standard deviation (mean ± SD) and were compared via one-way analysis of variance (ANOVA). Meanwhile, nonnormally distributed variables are expressed as the median and interquartile range and were compared with the Kruskal-Wallis test. Categorical variables are expressed as counts and percentages and were compared between groups with the Chi-squared test or the Fisher exact test; the post hoc test was performed with the least significance difference test. Two-way ANOVA was used for repeated measures, testing for the difference between and within the groups, and for determining the time-group interaction effect. A P value <0.05 was considered statistically significant.

Results

In total, we evaluated 171 patients for inclusion, among whom 156 were deemed eligible and randomized into groups. However, three patients were converted to thoracotomy during surgery, two patients had a poor perioperative oxygenation situation, and six patients were lost to follow-up postoperatively, all of whom were excluded. Ultimately, 145 patients were included in the study (Figure 1).

Figure 1 Flowchart of the study design. Group K1: low-dose esketamine group. Group K2: high-dose esketamine group. Group C: control group. SpO₂, pulse oxygen saturation.

There were no differences in baseline characteristics (age, sex, BMI, ASA physical status classification, or comorbidities) between the three groups (all P values >0.05) (Table 1); however, there were no significant differences in perioperative characteristics (surgery duration, OLV time, duration of anesthesia, opioid usage, etc.) (all P values >0.05) (Table 1).

The a/A ratio reflecting pulmonary gas exchange function

As shown in Figure 2A, we observed an obvious decrease in a/A ratio at the beginning of mechanical ventilation and OLV in all three groups, followed by a gradual increase at the end of surgery. The a/A ratio of the K1 and K2 groups recovered fully to the preoperative level and was significantly higher at T7 and T8, but that of group C was still significantly lower than the preoperative level and lower than that of the esketamine groups at T7 (C vs. K1 vs. K2: 64.5±3.6 vs. 83.2±3.6 vs. 79.7±3.5; F=7.801; P=0.001) and T8 (C vs. K1 vs. K2 = 64.7±18.2 vs. 84.4±18.8 vs. 82.6±17.8; F=9.961; P<0.001) [ANOVA: P_(group)<0.05, P_(time)<0.05, P_{(group × time)}<0.05]. There were no significant differences between the K1 and K2 groups (P>0.05; Figure 2A).

Figure 2 Changes in a/A ratio and other variables reflecting pulmonary gas exchange function at various time points. (A) a/A ratio. (B) RI. (C) OI. (D) A-aDO₂. ^#, P<0.05 in group K1 versus C. *, P<0.05 in group K2 versus C. A-aDO₂, alveolar arterial partial pressure difference of oxygen; a/A ratio, arterial-alveolar oxygen partial pressure ratio; ANOVA, analysis of variance; ICU, intensive care unit; OI, oxygenation index; OLV, one-lung ventilation; RI, respiratory index; T0, before anesthesia; T1, after intubation; T2, 30 minutes after OLV; T3, 1 h after OLV; T4, 15 minutes after the resumption of two-lung ventilation; T5, admission to the ICU; T6, after extubation; T7, discharge from ICU; T8, 24 h postoperatively.

Other variables reflecting pulmonary gas exchange function

The perioperative changes of the RI, OI, and A-aDO₂ ratio are shown in Figure 2B-2D, respectively. RI and A-aDO₂ ratio significantly increased and OI significantly decreased from 30 minutes after OLV (T2) to tracheal catheter removal (T6) in all groups, and there were no significant differences between three groups at the aforementioned time points. In contrast, at T7 and T8, the RI and A-aDO₂ ratio were significantly lower while OI was significantly higher in both the K1 and K2 groups in comparison with group C (all P values <0.05). However, no statistically significant differences were observed between the K1 and K2 groups in terms of the RI, OI, or A-aDO₂ ratio at any time point (all P values >0.05).

The Vd/Vt outcome reflecting pulmonary ventilation function

We observed a significant increase in alveolar dead space fraction after OLV and a peak at T4 in the K1 and C groups (P<0.05), but we did not observe a significant change in the K2 group, whose alveolar dead space fraction was significantly lower than that of the K1 and C groups at T3 (C vs. K1 vs. K2: 19.5±4.3 vs. 19.4±5.4 vs. 15.6±5.4; F=5.454; P=0.006) and T4 (C vs. K1 vs. K2: 22.7±4.5 vs. 20.3±6.7 vs. 15.4±5.7; F=12.444; P<0.001) [ANOVA: P_(group)<0.05, P_(time)<0.05, P_{(group × time)}<0.05] (Figure 3A).

Figure 3 Indicators reflecting pulmonary Vd/Vt, Cst, and Cdyn at various time points. (A) Vd/Vt. (B) Cst. (C) Cdyn. *, P<0.05 in group K2 versus the other two groups. ANOVA, analysis of variance; Cdyn, dynamic lung compliance; Cst, static lung compliance; OLV, one-lung ventilation; T1, after intubation; T2, 30 minutes after OLV; T3, 1 hour after OLV; T4, 15 minutes after the resumption of two-lung ventilation; Vd/Vt, dead space fraction.

The variables reflecting pulmonary respiratory mechanics

The Cst and Cdyn decreased significantly in all three groups after OLV, but Cst in group C was not significantly different compared with that in the K1 and K2 groups at the same time point (P>0.05; Figure 3B). Cdyn was higher in group K2 than in group C and group K1 at T2 [F=3.667; P=0.03; ANOVA: P_(time)<0.05] but was not significantly different between group C and group K1 (P>0.05; Figure 3C).

Intraoperative hemodynamics

The intraoperative mean arterial pressure (MAP) and heart rate in all three groups decreased after anesthesia, but group K1 and group K2 fluctuated less than did group C (P<0.05). Specifically, group C had a significantly lower MAP and heart rate at T1–T4 than did group K2 (P<0.05). In addition, the heart rate at T2 and T4 in group K1 was lower than that of group K2 (P<0.05), but the intraoperative blood pressure was not significantly different between the two esketamine groups (P>0.05) (Table 2).

Postoperative pain scores

Postoperative pain scores were self-reported by patients via the NRS at 24 and 48 hours after surgery. Lower rest and movement NRS pain scores were reported in group K1 than in group C at 24 and 48 hours after surgery; meanwhile, the rest and movement NRS pain scores in group K1 were significantly lower than those in group K2 at 48 hours postoperatively but not at 24 hours (Table 3).

Incidence of PPCs

PPCs occurred in 25 patients (52.1%) in group C, only 13 patients (27.1%) in group K1, and 11 patients (22.9%) in group K2, with the incidence being significantly higher in group C than in the K1 and K2 groups (P=0.006) and similar between the K1 and K2 groups (P>0.05). The most common PPC was postoperative respiratory failure (respiratory failure was defined as SpO₂ below 90% on room air), with incidence rates of 45.8%, 20.8%, and 20.4% in the C, K1, and K2 groups, respectively; the incidence in group C was significantly higher than that in the K1 and K2 groups (P=0.007) but not significantly different between the K1 and K2 groups (P>0.05) (Table 4).

Postoperative adverse events and inflammatory biomarkers

The distribution and incidence of adverse events in each group are shown in Table 5. In our study, a few patients in the esketamine groups experienced psychiatric adverse reactions postoperatively (specifically, negative emotional dream experiences such as fear, anxiety, and unease during their sleep after surgery and agitation during extubation). Esketamine-related adverse reactions occurred in only three patients in group K1 (one with postoperative nightmares and two with agitation during extubation) and in four patients in group K2 (two with postoperative nightmares and two with agitation during extubation). These patients’ symptoms soon resolved spontaneously or improved after intramuscular injection of morphine. Moreover, these adverse events did not represent a statistically significant difference (all P values >0.05), and there were no significant differences between the three groups in terms of the incidence of nausea or vomiting (P>0.05).

Tracheal extubation and length of ICU and hospital stays did not differ significantly between the three groups (P>0.05). Postoperative inflammatory indices were similarly elevated in all three groups (P>0.05) (Table 5).

Discussion

In this randomized controlled trial on patients undergoing VATS, we found that perioperative esketamine was associated with a significant lung-protective effect, as indicated by an improvement in pulmonary gas exchange function. In addition, patients in the esketamine groups had significantly lower postoperative rest and movement pain scores, more stable hemodynamics, and a lower incidence of PPCs. However, the different induction doses of 0.5 mg/kg and 1.0 mg/kg provided similarly beneficial effects in lung-protective function.

The Vd/Vt reflects lung ventilation function, with a higher Vd/Vt indicating worse lung ventilation function (21). Lung compliance represents the volume response to a unit change in pressure and is a sensitive indicator of lung injury and ventilation function. Improving lung compliance, reducing respiratory work, and promoting gas exchange are critical in patients undergoing general anesthesia (22). Compared with the K1 and C groups, group K2 had a lower Vd/Vt at the T4 and T3 time points and a higher Cdyn at the T2 time point. The a/A ratio and A-aDO₂ directly reflect the difference in oxygen partial pressure between the alveoli and arterial blood, serving as important indicators for evaluating pulmonary gas exchange and alveolar diffusion function, and can directly reflect the extent of lung injury (23,24). A lower a/A ratio and higher A-aDO₂ indicate poorer alveolar ventilation function. The OI and RI are both important indicators for comprehensively assessing a patient’s oxygenation function and pulmonary ventilation function. A lower OI and higher RI indicate that the patient has impaired oxygenation function (25-27). Subsequently, we compared these gas exchange function indicators between the three groups and found that compared with group C, groups K1 and K2 had a lower A-aDO₂ and RI at both the T7 and T8 time points, along with a higher a/A ratio and OI. However, there was no difference between the K2 and K1 groups. Overall, our study indicates that esketamine can improve intraoperative lung compliance and ventilation function in patients undergoing VATS, as well as improve postoperative oxygenation and lung function.

These observations may be the result of ketamine’s bronchodilatory effect, which is achieved by blocking NMDA-induced bronchoconstriction and catecholamine reuptake into presynaptic sympathetic neurons. Additionally, it exerts a bronchodilatory effect on bronchial smooth muscle through vagal inhibition, thereby reducing airway resistance, alleviating the degree of ventilation-perfusion mismatch, and increasing lung compliance and oxygenation capacity (28). In some case reports on asthma, esketamine was found to reduce airway resistance and improve lung compliance and has been approved as a rapid tracheal intubation induction drug for patients with bronchial asthma (29-30). Esmailian et al. (31) found that in patients with mild-to-moderate asthma, administration of 0.4–0.5 mg/kg doses of ketamine could relieve asthma symptoms by improving the peak expiratory flow rate. Given that esketamine has a similar mechanism of action to that of ketamine, this is consistent with our study results, which indicated that esketamine can improve postoperative lung function in patients undergoing thoracoscopy, with its primary mechanism of action likely being related to its bronchodilatory effects. Additionally, we found that different doses of esketamine do not have the same effect on the indicators of respiratory mechanics, and further research is required to clarify this relationship.

Patients undergoing VATS are prone to hypertension and poor hemodynamic stability, and the unstable hemodynamics adversely affect the oxygenation situation. Esketamine can increase heart rate and cardiac output through its properties of sympathetic stimulation, analgesia, and antagonism (32). Te et al. (10) reported that combining low-dose esketamine with a conventional anesthetic for anesthesia induction in older adults undergoing knee arthroplasty reduced the incidence of hypotension and was more hemodynamically stable, which is in accordance with our findings.

Although the related mechanism has not been completely clarified, the analgesic effects of esketamine have been well established by research. Helmar et al.’s study demonstrated that minimal-dose esketamine (0.015 mg/kg/h of continuous intravenous infusion) for 48 hours can achieve optimal postoperative analgesia and minimize the risk of the corresponding complications (33). In Helena et al.’s study, intravenous use of esketamine combined with thoracic paravertebral nerve block reduced pain scores at 48 hours postoperatively (34). In a recent trial, a single subanesthetic dose of esketamine administered after induction of anesthesia was found to alleviate pain and improve postoperative recovery quality scores in patients following thoracoscopic lung resection (35). In our study, 0.5 mg/kg of esketamine reduced pain scores in patients subjected to thoracoscopy 48 hours postoperatively. Moreover, this lower pain potentially contributed to early activity and sputum removal in patients, which further promotes the recovery of pulmonary function.

The anti-inflammatory effect of esketamine may be another mechanism by which esketamine improves postoperative lung function in patients undergoing VATS. Surgical manipulation causes the damaged cells to release cytoplasmic substances, which can trigger an inflammatory cascade by activating the corresponding receptors. Meanwhile, lung re-expansion after OLV leads to local neutrophil recruitment, enhanced pulmonary myeloperoxidase activity, increased vascular permeability, and pulmonary edema. In turn, this causes a systemic inflammatory response with elevated levels of inflammatory cytokines such as interleukin-6 (IL-6) and IL-1 (36,37). Previous studies have shown that esketamine can produce systemic anti-inflammatory effects by inhibiting the production of inflammatory factors, including IL-6 and tumor necrosis factor-α (TNF-α), and neutrophil activation (38). Welters et al.’s study showed that the use of esketamine as the only analgesic during coronary artery bypass surgery significantly reduces the abundance of pro-inflammatory cytokines IL-6 and IL-8 after aortic opening and elevates levels of the anti-inflammatory factor IL-10 (39). This suggests that esketamine may act as an immunomodulatory agent in thoracoscopic partial pneumonectomy, mitigating lung injury and protecting lung function by suppressing the inflammatory response. Although no significant differences in postoperative inflammatory biomarkers were found between the three groups of patients in our study, this may be related to our small sample size and the fact that we monitored systemic inflammation-related indicators rather than inflammatory indicators associated with lung injury.

The use of NMDA receptor antagonists is limited due to their associated adverse mental events. Esketamine induces fewer adverse reactions than does racemic ketamine. In our study, only a few patients (three patients in group K1 and four patients in group K2) experienced adverse mental events, and there was no statistically significant difference in the incidence of adverse mental events between the three groups. We speculate that this is because midazolam injection was routinely used in this study, and benzodiazepines have anxiolytic and amnesic effects, which thus reduced the incidence of related psychiatric adverse reactions in the esketamine group. The results of this study indicate that the use of these two doses of esketamine is relatively safe.

Limitations

Our study involved several limitations that should be addressed. First, the incidence of PPCs in our study was relatively high, which may be attributed to two possible causes: First, we adopted relatively broad diagnostic criteria, with the definition of respiratory complications encompassing mild and early respiratory dysfunction, including early imaging changes and related symptoms, which resulted in a relatively high incidence rate. Second, the sample size was small, and individual high-risk cases had a significant impact on the overall complication rate, rendering the incidence rate more prone to fluctuations. Second, although we implemented the same and adequate postoperative pain management measures, there were statistically significant differences in NRS scores between the three groups at 24 hours postoperatively, and pain might have influenced the results of respiratory mechanics testing. Third, we conducted this prospective randomized controlled trial at a single center with a small sample size, and the observed indicators were not comprehensive, as some long-term clinical symptoms were not yet evident. Therefore, additional multicenter, large-sample studies with a more comprehensive array of indicators are required to further confirm the lung-protective effects of esketamine on patients undergoing VATS. Fourth, we did not observe differences in lung function-related indicators between the two different dose groups. This may be because the selected indicators failed to capture important variability in lung function, and further dose-stratified studies will help clarify the relationship between dose and efficacy. Fifth, we hypothesize that the protective effect of esketamine on lung function may be related to its anti-inflammatory effects; however, we did not observe any differences in the inflammatory factors associated with lung injury. The changes in inflammatory factors in this study remain to be confirmed through further investigation.

Conclusions

We found that esketamine can improve oxygenation, alleviate lung injury, provide pulmonary protection, and reduce postoperative rest and movement pain scores in patients undergoing VATS. However, there were no differences between the two doses of esketamine administered in terms of improving postoperative length of ICU stay or hospital stay. Meanwhile, although esketamine was not associated with a significant difference in postoperative adverse mental reactions, this relationship should be evaluated in future studies.

Acknowledgments

The authors express their gratitude to Jinbao Guo (Thoracic Surgeon, The First Affiliated Hospital of Chongqing Medical University) for assisting with data collection.

Footnote

Reporting Checklist: The authors have completed the CONSORT reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-999/rc

Trial Protocol: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-999/tp

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-999/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-999/prf

Funding: This work was supported by grants from National Key Clinical Specialty Construction Project (No. 2011-170).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-999/coif). All authors report that this work was supported by grants from National Key Clinical Specialty Construction Project (No. 2011-170) and the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The First Affiliated Hospital of Chongqing Medical University (No. 2021-318) and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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