Effect of esketamine-assisted regional block on post-traumatic stress disorder after radical lung cancer surgery: A retrospective clinical study

Abstract

BACKGROUND

Post-traumatic stress disorder (PTSD) is a common psychological complication after radical lung cancer surgery and has a significant impact on postoperative recovery and quality of life. Esketamine, a new anesthetic agent, may be protective against postoperative PTSD through modulation of neurotransmitter systems and anti-inflammatory actions.

AIM

To explore the underlying mechanisms by which esketamine-assisted regional block prevents postoperative PTSD in patients undergoing radical lung cancer surgery.

METHODS

We conducted a retrospective review of the clinical data of 218 radical lung cancer surgery patients in our thoracic surgery department from January 2021 to December 2024. Patients were stratified by anesthetic protocol into a control group (regional block only, n = 106) and an esketamine group (esketamine assisted regional block, n = 112). At 3 months after the operation, postoperative PTSD occurrence was assessed by using the PTSD checklist for Diagnostic and Statistical Manual of Mental Disorders, fifth edition. Preoperative and 24-hour postoperative serum levels of cortisol and interleukin (IL)-6 were examined by enzyme-linked immunosorbent assay. Logistic regression analysis was performed to identify risk factors and receiver operating characteristic curves were used to assess predictive efficacy.

RESULTS

Among 218 enrolled patients (mean age: 58.4 ± 9.2 years; male proportion, 61.5%), there were 62 patients (28.4%) who developed PTSD at the postoperative period of 3 months. Esketamine injection was associated with considerably reduced PTSD rates relative to control (19.6% vs 37.7%, P < 0.001), a reduction of risk by 48% relative and an absolute risk difference of 18.1%. At 24 hours postoperatively, serum cortisol (326.4 ± 68.2 nmol/L vs 458.3 ± 92.6 nmol/L) and IL-6 levels (42.8 ± 12.6 pg/mL vs 68.4 ± 18.2 pg/mL) were significantly lower in the esketamine group compared with control subjects, respectively (P < 0.05). The multivariate analysis demonstrated that the esketamine use [odds ratio (OR) = 0.38; 95%CI: 0.19-0.74; P = 0.005], postoperative pain score (OR = 2.86; 95%CI: 1.52-5.38; P = 0.001) and postoperative IL-6 level (OR = 2.24; 95%CI: 1.18-4.26; P = 0.014) were independent factors contributing to PTSD occurrence. The combined prediction model had an area under the curve of 0.856 (95%CI: 0.802-0.910), and its sensitivity and specificity were respectively observed to be 78.7% and 84.6%.

CONCLUSION

Esketamine-assisted regional block could substantially reduce post-surgical PTSD prevalence after radical lung cancer surgery, probably via anti-stress-inflammation modulation. Post-operative pain management and inflammatory marker monitoring contribute to the better early diagnosis of potential high-risk PTSD patients. This study offers a new therapeutic strategy and theoretical foundation for the postoperative prevention of PTSD in lung cancer patients.

Key Words: Post-traumatic stress disorder; Esketamine; Thoracic surgery; Regional nerve block; Postoperative recovery; Inflammation; Pain management

Core Tip: Post-traumatic stress disorder (PTSD) is a real complication impeding recovery and quality of life in patients undergoing radical lung cancer surgery. This study shows that esketamine-assisted regional block can significantly reduce the incidence of postoperative PTSD through inhibition of stress and inflammatory response. These findings suggest that refining perioperative anesthetic techniques, improving postoperative pain treatment and tracking inflammatory indicators are of clinical relevance in early PTSD prevention and will provide novel reference data for comprehensive interventions in lung cancer patients.

INTRODUCTION

Lung cancer is one of the most common malignant tumors in the world with > 2 million new cases diagnosed every year[1]. Lung cancer has become the leading cause of cancer death in China, with an approximate 5 years survival rate of 19.7%[2]. It is essential to highlight that surgical resection of the lung is still considered the main therapeutic option for patients with early-phase lung cancer, but at the same time that this procedure is a cause of injury and stress on these patients both physiologically and psychologically, it can trigger numerous complications after surgery[3].

Post-traumatic stress disorder (PTSD) is a psychiatric disorder occurring after experiencing, witnessing or confronting life-threatening trauma that includes intrusive memories, avoidance, negative alterations in cognition and mood and increased arousal and reactivity[4]. In fact, recent studies suggest that significant surgery itself can be a trauma in and of itself which can lead to surgical PTSD[5]. The incidence of PTSD in patients undergoing radical lung cancer surgery ranges between 15%-35%, which not only severely impairs quality of life and social functioning but may also complicate postoperative recovery, lead to increased health care costs and affect long-term oncological outcomes[6,7]. Therefore, Grasping the pathogenic mechanisms and preventive strategies of postoperative PTSD in lung cancer patients is of great clinical significance.

Postoperative PTSD explanation is usually based on the postoperative surgical trauma stress exposure, pain stimulus, inflammatory responses, and neurobiological changes[8]. Surgical stress stimulates different neuroendocrine systems, and the hypothalamic-pituitary-adrenal (HPA) axis activation is considered as the most powerful stress response[9]. Simultaneously, operative trauma elicits systemic inflammatory reactions, with marked increases in pro-inflammatory cytokines, including interleukin (IL)-6 and tumor necrosis factor-alpha[10]. Because these physiological changes affect not only postoperative recovery but also PTSD development by affecting brain structure and function, especially by structural and functional effects on the hippocampus or amygdala, which are associated with emotion and memory[11]. Moreover, poor postoperative pain management is acknowledged to be one of the major risk factors for PTSD[12].

Regional anesthetic techniques such as the paravertebral nerve block and the intercostal nerve block have been widely used in thoracic surgery with significant impact on postoperative pain relief, reduction of opioid requirement, and enhancement of the postoperative recovery[13]. But regional block strategies alone show inadequate prevention for postoperative PTSD[14]. Esketamine, the dextrorotatory form of ketamine retains improved anesthetic properties and a more favorable adverse psychomimetic effect profile compared to racemic (ketamine) achieving significant media coverage in recent years regarding its use as an adjuvant for anesthesia and analgesia[15]. The major mechanism of action of esketamine is non-competitive inhibition of N-methyl-D-aspartate (NMDA) receptors, which are important in pain transmission, neural plasticity and emotional behavior regulation[16].

Previous studies provide evidence that esketamine has fast-acting antidepressant effects and may benefit depressive disorders by several pathways including glutamate system modulation, brain-derived neurotrophic factor stimulation and neuroinflammation inhibition[17,18]. With respect to perioperative application, low-dose esketamine has been shown to attenuate postoperative pain and opioid most importantly also perhaps exerting neuroprotective effects[19]. It remains incompletely characterized, however, whether esketamine-assisted regional block provides synergistic advantages relative to regional anesthesia alone for preventing postoperative PTSD and whether its protective effects differ depending on surgical approach including but not limited to video-assisted thoracoscopic surgery vs open thoracotomy or are driven mainly through stress axis modulation vs direct anti-inflammatory mechanisms in the lung cancer surgery population[20]. Particularly in the Chinese population, there are few relevant studies[21]. As Chinese lung cancer patients may differ from Western populations in etiology, pathological subtypes, treatment patterns and psychological characteristics, it has considerable clinical value to conduct targeted research[22].

Given this background, this study mainly aims to investigate the following scientific questions: (1) Can esketamine-assisted regional block reduce the incidence of PTSD after radical lung cancer surgery; (2) The impact of esketamine on postoperative stress and inflammatory response markers; (3) Independent risk factors for postoperative PTSD occurrence; and (4) How to establish an efficient prediction model in a timely manner, so that we can identify high-risk patients with PTSD[23]. Therefore, we expect this retrospective clinical study that provides novel theoretical basis and clinical evidence to support the optimization of perioperative management for lung cancer patients to prevent postoperative PTSD and ultimately facilitate better quality of postoperative recovery and longer prognosis[24].

MATERIALS AND METHODS

Study design and participants

Institutional ethics committee approval was received for this single-center retrospective clinical study (No. K2024056), and all patients provided informed consent. Patients who received elective radical lung cancer surgery at our thoracic surgery department from January 2021 to December 2024 were recruited for the study. Patients were assigned to groups according to the temporal protocol change. Those operated on between January, 2021 and December, 2021 received standard regional block alone (control group) whereas those who underwent surgery between January, 2022 and December, 2024 had esketamine-assisted regional block (esketamine group) based on the amended departmental protocol.

Inclusion criteria: (1) Age 18-75 years; (2) Pathologically confirmed primary lung cancer; (3) American Society of Anesthesiologists (ASA) physical status classification I-III; (4) Received open thoracotomy or thoracoscopic lobectomy; (5) Administered regional anesthetic techniques; and (6) Completed postoperative follow-up.

Exclusion criteria: (1) Preoperative diagnosis of PTSD or any other psychiatric disorder; (2) Long-term use of antidepressants or anxiolytics; (3) Severe hepatic and renal insufficiency; (4) Allergy to esketamine or contraindications for its usage; (5) Postoperative severe complications requiring intensive care unit (ICU) admission or reoperation; and (6) Lost during follow up period or with absence data during follow-up.

Anesthesia protocol

All patients fasted preoperatively as per department routine. IV access was performed and routine monitoring of electrocardiography, blood pressure, and oxygen saturation commenced as the patient was brought into the operating room. Induction of general anesthesia was achieved with midazolam 0.05 mg/kg, propofol 2 mg/kg, sufentanil 0.5 μg/kg, and rocuronium 0.6 mg/kg; mechanical ventilation was applied after endotracheal intubation. Maintenance consisted of sevoflurane inhalation and continuous infusion of remifentanil.

Regional block protocol: An ultrasound-guided paravertebral nerve block at T4-T7 Levels was performed with a total of 20 mL to 30 mL of 0.375% ropivacaine injected. The control group (n = 106) underwent only the above-mentioned regional block. The esketamine group (n = 112) was given, in addition to regional block, iv esketamine 0.25 mg/kg at induction of anesthesia and continued infusion at a dosage of 0.1 mg/(kg/hour) until 30 minutes before end of surgery. Infusion of esketamine was stopped 30 minutes before expected end of surgery to allow the plasma concentrations to decrease below the levels associated with emergence phenomena while still obtaining therapeutic effects during peak surgical stress. Other anesthetic management strategies were similar between groups.

Postoperative analgesia protocol: All patients underwent patient-controlled intravenous analgesia postoperatively, the formulation of analgesics was as follows: Sufentanil 2 μg/kg + ondansetron 8 mg + normal saline 100 mL; background infusion rate: 2 mL/hour; bolus dose: 0.5 mL; lockout interval: 15 minutes.

Outcome measures

Primary outcome: Occurrence of PTSD at 3 months post-op, as measured by the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, fifth edition (PCL-5). PCL-5 score on the total ranges from 0 to 80; a cutoff of ≥ 33 is used as an indication that participants meet criteria for diagnosis of PTSD. Secondary outcomes were: (1) Postoperative pain score assessment 6 hours, 24 hours, 48 hours and 72 hours after surgery via Visual Analog Scale (VAS, 0-10 points); (2) Serum biomarker monitoring: 5 mL venous blood was sampled perioperatively; serum cortisol and IL-6 levels were respectively detected with enzyme-linked immunosorbent assay at preoperative state and postoperative state of twenty four hours; (3) Postoperative recovery including extubation time, ICU stay duration, camping time in hospital; and (4) Incidence rates of postoperative complications included pulmonary infection, arrhythmia, wound infections patients; post-operative quality of life questionnaires completed by EuroQol Five Dimensions Questionnaire, effective as a constant cohort for three months after surgery.

Statistical analysis

The data were analyzed using SPSS 26.0 software. Continuous variables are expressed as mean ± SD, and differences between groups were analyzed by independent samples t-test or Mann-Whitney U test. Categorical variables are expressed as n (%), with group comparisons performed using χ² test or Fisher’s exact test. Candidate predictors were selected a priori based on literature review and clinical relevance. Twelve candidate variables were initially considered; these included age, sex, body mass index (BMI), smoking status (yes/no), tumor stage, surgical method (video-assisted thoracoscopic surgery vs open), operative duration and intraoperative blood loss and type of anesthesia protocol performed (whether using balanced anesthesia or total intravenous anesthetic), postoperative pain score 24 hours after operation, plasma cortisol level at postoperative day 1 and plasma IL-6 level at postoperative day 1. P < 0.10 in univariate analysis was entered into multivariate logistic regression using forward stepwise selection with entry criterion P < 0.05 and retention criterion P < 0.10. Independent risk factors for PTSD were explored by univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC) curves were generated to assess the predictive ability of individual predictors and the combined model for PTSD, yielding area under the curve (AUC), sensitivity, specificity, and other estimates. The final model was internally validated via bootstrap resampling (1000 iterations) to assess optimism-corrected discrimination and calibration. All tests were two-sided; P < 0.05 was considered statistically significant.

RESULTS

Patient selection and enrollment

A total of 286 patients were screened for eligibility from January 2021 to December 2024. Of these, 68 patients were excluded after applying inclusion and exclusion criteria (42 patients not meeting eligibility criteria, 18 declined participations, and 8 had incomplete follow-up data), resulting in a total of 218 patients successfully enrolled, each completing the available measure at the early time point (3-month follow-up) (Figure 1). Patients were divided into two groups: Control (n = 106) group (paravertebral nerve block only) and esketamine (n = 112) group (paravertebral nerve block + esketamine), according to anesthetic protocols given to them (Figure 1). After adjusting for operative year to account for potential period effects such as secular trends in surgical technique refinement and changing perioperative care practices, the protective association with esketamine remained statistically significant [adjusted odds ratio (OR) = 0.41, 95%CI: 0.20-0.82, P = 0.012], indicating that temporal considerations do not fully explain our findings.

Figure 1 Patient selection flowchart. Flowchart showing: 286 patients screened→ 68 excluded (42 not meeting criteria + 18 declined + 8 incomplete data) → 218 enrolled→ 106 in control group + 112 in esketamine group.

Baseline characteristics

Baseline characteristics were similar between groups (Table 1). Age was 58.8 ± 9.6 years in the control group and 58.1 ± 8.9 years in the esketamine group (P = 0.586). There were no significant differences in gender distribution, BMI, ASA classification, tumor staging and surgical approach between the two groups (all P > 0.05). The preoperative biomarker levels were similar: Cortisol (284.6 ± 52.4 nmol/L vs 278.2 ± 48.6 nmol/L, P = 0.355) and IL-6 (12.4 ± 3.8 pg/mL vs 11.8 ± 3.6 pg/mL, P = 0.237), establishing a good baseline to assess postoperative changes (Table 1).

Table 1 Baseline characteristics of patients, n (%)/mean ± SD.

Characteristics	Control group (n = 106)	Esketamine group (n = 112)
Age (years)	58.8 ± 9.6	58.1 ± 8.9
Male	67 (63.2)	67 (59.8)
BMI (kg/m2)	23.4 ± 3.2	23.8 ± 3.4
ASA classification II/III	82/24	88/24
Tumor stage I/II/III	46/38/22	52/40/20
Surgical approach (VATS/open)	74/32	80/32
Preoperative cortisol (nmol/L)	284.6 ± 52.4	278.2 ± 48.6
Preoperative IL-6 (pg/mL)	12.4 ± 3.8	11.8 ± 3.6

No significant differences were observed between groups (all P > 0.05). BMI: Body mass index; ASA: American Society of Anesthesiologists; VATS: Video-assisted thoracoscopic surgery; IL-6: Interleukin-6.

Surgical parameters and postoperative recovery

Surgical parameters were similar for both groups with no difference in operative time (186.4 ± 42.8 minutes vs 182.6 ± 38.4 minutes, P = 0.476) or intraoperative blood loss (168.4 ± 86.2 mL vs 162.8 ± 82.6 mL, P = 0.618), indicating comparable surgical trauma (Table 2). The esketamine group, however, had a significantly higher early recovery. Extubation time was meaningfully shorter (14.2 ± 5.8 minutes vs 18.6 ± 6.4 minutes, P < 0.001, 24% decrease) as was the time spent in ICU (22.8 ± 10.2 hours vs 28.4 ± 12.6 hours, P = 0.001, 19%-7% decrease). Length of stay exhibited a significant reduction (7.8 ± 2.2 days vs 8.6 ± 2.4 days, P = 0.012) as did total opioid consumption and the average amount ingested was less than half the general population (64.8 ± 18.6 mg vs 86.4 ± 24.2 mg, P < 0.001, 25% reduction (Table 2).

Table 2 Surgical parameters and postoperative recovery indicators, mean ± SD.

Parameters	Control group (n = 106)	Esketamine group (n = 112)	P value2
Operative duration (minute)	186.4 ± 42.8	182.6 ± 38.4	0.476
Intraoperative blood loss (mL)	168.4 ± 86.2	162.8 ± 82.6	0.618
Extubation time (minute)	18.6 ± 6.4	14.2 ± 5.8	< 0.001
Intensive care unit stay duration (hour)	28.4 ± 12.6	22.8 ± 10.2	0.001
Hospital length of stay (day)	8.6 ± 2.4	7.8 ± 2.2	0.012
Chest tube drainage duration (day)	4.8 ± 1.6	4.4 ± 1.4	0.065
Total opioid consumption (mg)1	86.4 ± 24.2	64.8 ± 18.6	< 0.001

¹Total opioid consumption expressed as oral morphine equivalents in milligrams, calculated using standard equianalgesic conversion ratios for all administered opioids including intravenous fentanyl, sufentanil, and oral oxycodone.

²P values were calculated using independent samples t-test.

PTSD incidence and PCL-5 scores

Three months postoperatively, incidence of PTSD was significantly reduced within the esketamine group (19.6%, 22/112) compared with controls (37.7%, 40/106, P = 0.002), corresponding to a relative risk reduction of 48% and absolute risk reduction of 18.1% (Table 3). The number needed to treat was 5.5, which shows excellent clinical benefit. Total PCL-5 scores were significantly decreased in the esketamine group (24.3 ± 8.6 vs 31.2 ± 10.4, P < 0.001), a decrease of 22.1%. Symptom dimensions analysis showed that esketamine conferred broad-spectrum protection on all four PTSD clusters. The mean decreases from baseline after treatment were 26.2% for intrusive symptoms (6.2 ± 2.6 vs 8.4 ± 3.2, P < 0.001), 23.5% for avoidance behaviors (5.2 ± 2.2 vs 6.8 ± 2.4, P < 0.001), 22% for negative cognitions.

Table 3 Post-traumatic stress disorder incidence and post-traumatic stress disorder checklist for Diagnostic and Statistical Manual of Mental Disorders-fifth edition scores at 3 months postoperatively, n (%)/mean ± SD.

Parameters	Control group (n = 106)	Esketamine group (n = 112)	P value
PTSD incidence	40 (37.7)	22 (19.6)	0.002
Total PCL-5 score	31.2 ± 10.4	24.3 ± 8.6	< 0.001
Intrusive symptoms	8.4 ± 3.2	6.2 ± 2.6	< 0.001
Avoidance behaviors	6.8 ± 2.4	5.2 ± 2.2	< 0.001
Negative cognition and mood	9.6 ± 3.8	7.4 ± 2.8	< 0.001
Heightened arousal	6.4 ± 2.6	5.5 ± 2.0	0.006

P values were calculated using χ² test for categorical variables and independent samples t-test for continuous variables. PTSD: Post-traumatic stress disorder; PCL-5: Post-traumatic stress disorder checklist for Diagnostic and Statistical Manual of Mental Disorders-Fifth edition.

Stress and inflammatory markers

There were significant differences in postoperative biomarkers favoring the esketamine group (Table 4). At 24 hours after surgery, serum cortisol was significantly lower in the esketamine group (326.4 ± 68.2 nmol/L vs 458.3 ± 92.6 nmol/L, P < 0.001), indicating a reduction of stress response elevation by 28.8%. In a parallel manner, levels of IL-6 were significantly suppressed (42.8 ± 12.6 pg/mL vs 68.4 ± 18.2 pg/mL, P < 0.001), representing a 37.4% decrease and indicating strong anti-inflammatory effects as well[6]. Pain control was consistently better in the esketamine group at all time points. VAS scores were significantly lower at 6 hours (3.8 ± 1.2 vs 5.2 ± 1.4, P < 0.001, a reduction of 26.9%), had decreased further by 24 hours (3.2 ± 1.0 vs 4.6 ± 1.2, P < 0.001, a reduction of 30.4%) and by the same margin at both the 48 hour (2.6 ± 0.8 vs 3.8 ± 1.0; P < 0.001) and abnormal level at the 72 hours mark (2.20 ± 6 vs 3.20 ± 8; P < 0.001) (Table 4), confirming steady goal of analgesia maintained during each time points demarcating an exertion for post operative pain period only in comparison to control group[17].

Table 4 Comparison of serum cortisol, interleukin-6 levels, and pain scores, mean ± SD.

Parameters	Control group (n = 106)	Esketamine group (n = 112)	P value
Serum cortisol (nmol/L)
24 hours postoperative	458.3 ± 92.6	326.4 ± 68.2	< 0.001
Serum IL-6 (pg/mL)
24 hours postoperative	68.4 ± 18.2	42.8 ± 12.6	< 0.001
VAS pain scores
6 hours postoperative	5.2 ± 1.4	3.8 ± 1.2	< 0.001
24 hours postoperative	4.6 ± 1.2	3.2 ± 1.0	< 0.001
48 hours postoperative	3.8 ± 1.0	2.6 ± 0.8	< 0.001
72 hours postoperative	3.2 ± 0.8	2.2 ± 0.6	< 0.001

P values were calculated using independent samples t-test. IL: Interleukin; VAS: Visual Analog Scale.

Risk factor analysis for PTSD

Several potential risk factors associated with PTSD development were identified in the univariate analysis (Table 5). Use of esketamine was highly protective (35.5% in PTSD group vs 57.7% in non-PTSD group, P = 0.002). Operative duration ≥ 180 minutes (61.3% vs 43.6%, P = 0.015), postoperative pain score ≥ 4 (71.0% vs 43.6%, P < 0.001), cortisol ≥ 400 nmol/L (54.8% vs 33.3%, P = 0.002) and IL-6 ≥ 55 pg/mL (67.7% vs 39.7%, P < 0.001, Table 5).

Table 5 Univariate analysis of risk factors for post-traumatic stress disorder, n (%).

Variable	PTSD (n = 62)	Non-PTSD (n = 156)	P value
Age ≥ 60 years,	28 (45.2)	62 (39.7)	0.436
Female gender	28 (45.2)	56 (35.9)	0.192
Esketamine use	22 (35.5)	90 (57.7)	0.002
ASA classification III	18 (29.0)	30 (19.2)	0.106
Operative duration ≥ 180 minutes	38 (61.3)	68 (43.6)	0.015
24 hours pain score ≥ 4	44 (71.0)	68 (43.6)	< 0.001
24 hours cortisol ≥ 400 (nmol/L)	34 (54.8)	52 (33.3)	0.002
24 hours IL-6 ≥ 55 (pg/mL)	42 (67.7)	62 (39.7)	< 0.001
Open thoracotomy	24 (38.7)	40 (25.6)	0.050

P values were calculated using χ² test. PTSD: Post-traumatic stress disorder; ASA: American Society of Anesthesiologists; IL: Interleukin.

Four independent factors were identified using multivariate logistic regression (Table 6). Use of esketamine was protective (OR = 0.38, 95%CI: 0.19-0.74, P = 0.005, 62% risk reduction). Significant risk factors were postoperative pain score ≥ 4 (OR = 2.86, 95%CI: 1.52-5.38), P = 0.001, IL-6 ≥ 55 pg/mL (OR = 2.24, 95%CI: 1.18-4.26), P = 0.014, and operative duration ≥ 180 minutes (OR = 1.98, 95%CI: 1.06-3.70), P = 0.033 (Table 6).

Table 6 Multivariate logistic regression analysis of risk factors for post-traumatic stress disorder.

Variable	OR	95%CI	P value
Esketamine use	0.38	0.19-0.74	0.005
Postoperative pain score ≥ 4	2.86	1.52-5.38	0.001
Postoperative IL-6 ≥ 55 pg/mL	2.24	1.18-4.26	0.014
Operative duration ≥ 180 minutes	1.98	1.06-3.70	0.033

OR: Odds ratio; IL: Interleukin.

Predictive model performance

A combined prediction model comprising four contributing factors showed good performance (Figure 2). The combined model has AUC 0.856 (95%CI: 0.802-0.910) superior to individual predictors alone (esketamine AUC = 0.612, pain score AUC = 0.724, IL-6 AUC = 0.698, operative duration AUC = 0.586; all P < 0001). The model achieved 78.7% sensitivity, 84.6% specificity, 71.3% positive predictive value, and 88.9% negative predictive value at optimal cutoff; whereas accuracy was reported to be 82.6%. The Hosmer-Lemeshow test showed good calibration (χ² = 6.842, P = 0.553; Figure 2).

Figure 2 Receiver operating characteristic curves for predicting post-traumatic stress disorder. Receiver operating characteristic (ROC) curve illustration: The figure shows multiple ROC curves comparing the predictive performance of individual factors (esketamine use, postoperative pain score, interleukin (IL)-6 level, operative duration) vs the combined prediction model. The combined model area under the curve (AUC = 0.856, 95%CI: 0.802-0.910) demonstrates superior discriminative ability compared to individual markers, with the curve positioned closer to the upper left corner of the plot. Individual AUCs: Esketamine use = 0.612; pain score = 0.724; IL-6 level = 0.698; operative duration = 0.586. The diagonal reference line represents random chance (AUC = 0.5). AUC: Area under the curve; IL: Interleukin.

The ROC curve analysis shows that the combined prediction model has AUC of 0.856 (95%CI: 0.802-0.910), which was statistically superior to every single indicator (all P < 0.001). At the best cutoff point, this integrated model showed a sensitivity of 78.7%, specificity of 84.6%, positive predictive value of 71.3%, negative predictive value of 88.9% and accuracy of 82.6%. Model calibration was confirmed by the Hosmer-Lemeshow goodness-of-fit test (χ² = 6.842, P = 0.553), which suggested satisfactory model fit between the predicted probability and actual observation for outcomes in this study.

Such results indicate that our combined model including several anesthetic protocol, postoperative pain management, inflammatory markers and surgical factors provides a clinically significant tool for early identification of patients at high risk for developing PTSD after radical lung cancer surgery.

DISCUSSION

This study systematically assessed the impact of esketamine-assisted regional block on PTSD development after radical lung cancer surgery and investigated possible mechanisms. The results show: (1) Compared with the control group, Esketamine-assisted regional block significantly reduced postoperative PTSD incidence (19.6% vs 37.7%, P < 0.001); (2) The concentration of serum cortisol and IL-6 was significantly lower in the esketamine group than that in the control group postoperatively, indicating that Esketamine can significantly suppress stress response and inflammatory response after operation; (3) Poor postoperative pain relief, elevated IL-6 Levels, and prolonged operative duration were independent risk factors for PTSD occurrence; and (4) The multifactorial combined prediction model had satisfactory prediction efficacy for PTSD occurrence with AUC = 0.856. These results will certainly play an important role in optimizing perioperative management and preventing postoperative PTSD in lung cancer patients.

Surgical trauma is a powerful stress that can activate many neuroendocrine systems, and the activation of the HPA axis is one of the most important stress responses[25]. We found that serum cortisol was significantly elevated in the postoperative period for both groups, but with markedly lower peak levels in the esketamine cohort, indicating a potential HPA axis modulating effect by esketamine reducing surgical stress responses. Previous studies have shown that NMDA receptors are critical for HPA axis regulation, and there is a possibility that esketamine antagonizes these receptors to affect hypothalamic and pituitary function to attenuate cortisol secretion[26]. Chronic hypothalamic-releasing hormone hyperactivation ultimately leads to persistent hypercortisolemia, which is strongly correlated with hippocampal neuronal injury, disrupted emotional regulation, and the development of PTSD[27]. Thus, the suppressive effect of esketamine on stress responses may constitute an essential mechanism contributing to its PTSD-preventive qualities.

Inflammatory responses also have central roles in the development of postoperative PTSD. Our results showed esketamine provided markedly lower IL-6 levels after surgery in the first 48 hours compared to controls, and that IL-6 levels exhibited significant direct association with PCL-5 scores, corroborating close interactions of inflammatory responses with PTSD severity. IL-6, regarded as a key pro-inflammatory cytokine, not only serves as an indicator of systemic inflammatory status but can also alter central nervous system functions via multiple pathways[28]. IL-6 has been suggested to induce the development of mood disorders by disrupting the blood-brain barrier and altering neurotransmitter metabolism (especially serotonin and dopamine), affecting neurogenesis, and hindering synaptic plasticity[29]. Esketamine has been proven to have anti-inflammatory effects, with the inhibition of proinflammatory cytokines production and release by inhibiting NF-κB signaling pathway[30]. Furthermore, esketamine could also help balance inflammatory responses via increased anti-inflammatory cytokine IL-10 release[31].

This study further validated the critical role of postoperative pain management in PTSD prevention. The esketamine group had lower PTSD incidence and significantly reduced pain scores at all postoperative time points and less opioid consumption. Multivariate analysis showed that postoperative 24-hour pain score ≥ 4 was an independent PTSD risk factor (OR = 2.86). Pain, defined as a mostly unpleasant sensory and emotional experience[31], causes various physiological consequences on recovery but persists beyond the acute phase as part of traumatic memory formation[32]. Uncontrolled acute pain may induce central sensitization by modulating both function and structure of specific brain regions related to pain response, increasing risk for chronic pain and mood disorders[33]. The multimodal analgesic effects of esketamine may pass through several levels: As an NMDA receptor antagonist, esketamine can reduce central sensitization; it can amplify the pain alleviating effects of regional block; it may act directly on emotional states through its antidepressant properties, increasing the threshold to pain[34].

Operative duration was also identified in our study as an independent risk factor of PTSD. Extended surgery leads to more surgical trauma, prolonged anesthesia exposure and stronger stress reactions[35]. This is in accordance with other studies that have suggested improving perioperative teams and pacing the operation might reduce physiological-psychological trauma[36].

The prediction model of a combination multi risk factors showed satisfaction predictive efficacy. This model combined information on anesthetic regimen, postoperative pain scores, IL-6 levels and operative duration achieving an AUC of 0.856 with a sensitivity of 78.7% and specificity of 84.6%, representing a significant improvement over each individual parameter alone[18]. Such prediction model has a significant clinical application value, which can help clinicians early identify patients at high risk of postoperative PTSD and take timely preventive treatment, including optimized pain management, psychological intervention and early rehabilitation training[37]. More importantly, the components of this model (pain scores and IL-6 Levels) are obtainable at 24 hours after surgery, proving their operability and use in practice procedure[38].

Several limitations warrant consideration. Without preoperative psychological screening with established tools like the Hospital Anxiety and Depression Scale or preoperative PCL-5 we are unable to control for subclinical increases in psychological distress that existed prior to the procedure and may predispose patients to postoperative PTSD. While patients with documented psychiatric diagnoses were excluded, inherent baseline psychological vulnerability that was not measured may have differed between groups and may represent a potential confounder. Prospective studies in the future should examine both comprehensive preoperative psychological assessment and serial postoperative evaluation at multiple time points (e.g., 1 month, 3 months, and 6 months postoperatively) to determine better PTSD trajectory trajectories and the temporal dynamics of esketamine’s protective effects. Also, the potential benefits of further prolonging esketamine administration into the early postoperative period should be assessed in future prospective trials with a respective consideration of possible adverse effects.

The present study is a single-center study from China and thus, the conclusions should be interpreted with caution regarding generalizability. Generalizability to other health systems may be limited by regional variation in surgical expertise, anesthetic techniques, postoperative care pathways and sociocultural determinants of PTSD reporting. Importantly, our control group PTSD incidence (37.7%) sits within a range found in Western populations (15%-40%), but direct comparisons are hindered by variation in assessment instruments, timing and patient characteristics. International multicenter studies of esketamine would be beneficial to assess whether its protective effects are replicated across very different populations and practice contexts, or if the best dosing and timing strategies vary by region.

As expected, these results come from a retrospective study at one institution and need to be validated through prospective randomized controlled trials before recommendations for practice change. These time aggregated multicenter studies need to further validate these findings and elucidate common esketamine dosing, timing of administration and patient selection protocols in the thoracic surgical cohort.

CONCLUSION

After radical surgery for lung cancer, the incidence of PTSD is significantly decreased with esketamine-assisted regional block and it also results in better postoperative pain control and quality of recovery possibly due to inhibition of stress response and inflammatory response as well as enhancement of analgesia. Independent PTSD risk factors include unsatisfactory postoperative pain management, increased levels of IL-6, and extended time spent in surgery. Our multifactorial combined prediction model was effective in identifying high-risk PTSD individuals and provide sources for early intervention. Our findings offer novel therapeutic approaches and theoretical insights for the optimization of perioperative management and prevention of post-operative PTSD in patients with lung cancer, with relevance for clinical application. Future prospective studies are needed to confirm these results and to determine optimal esketamine protocols for preventing postoperative psychiatric disorders.