Effect of epidural analgesia on the neutrophil-to-lymphocyte ratio after thoracic surgery: a large-scale retrospective cohort study

Introduction

Thoracic surgery, encompassing procedures on the lungs, esophagus, and mediastinum, is associated with significant postoperative pain and inflammatory responses (1,2), primarily resulting from acute tissue trauma and/or muscle ligament strain due to the surgical incision, intercostal neurovascular injury, inflammatory stress from disarticulation of the intercostal cartilage joints, and pleural irritation caused by the placement of chest drains (1). Inadequate management of postoperative pain in thoracic surgery can impede deep breathing and effective coughing, leading to the retention of airway secretions. This, in turn, adversely affects the recovery of pulmonary function and increases the incidence of pulmonary complications, such as lung infection, pulmonary atelectasis, pleural effusion, hypoxemia, and hypercapnia (3). Furthermore, insufficient control of acute postoperative pain may contribute to the development of chronic pain (4), significantly impacting patients’ quality of life, exacerbating psychological distress, extending hospitalization duration, increasing healthcare costs, and hindering early and rapid recovery. Effective postoperative analgesia is critical for patient recovery, mitigating complications, and facilitating early mobilization (5).

One of the primary mechanisms underlying postoperative pain is surgery-induced inflammation (6). Surgical manipulation triggers an inflammatory response characterized by leukocytosis, and the stress response associated with surgery has been implicated in the exacerbation of inflammation in patients (7). Epidural analgesia has been demonstrated to be an effective modality for pain relief (8), with evidence suggesting its capacity to partially mitigate surgery-induced immune alterations. Previous research has indicated that the combination of epidural anesthesia with general anesthesia can attenuate intraoperative sympathetic excitability and reduce the stress response (9). However, the role of epidural analgesia in modulating the inflammatory process during surgery remains unclear. The neutrophil-to-lymphocyte ratio (NLR) is recognized as an indicator of systemic inflammatory status. Research indicated that patients exhibiting elevated NLR demonstrate significant systemic inflammation prior to surgical intervention, potentially resulting in increased pain due to alterations in the inflammatory balance (10). Patients with pre-operative NLR levels exceeding two are associated with heightened pain scores and a greater need for analgesic medication following orthognathic surgery (11). A study on elective thoracotomy revealed that pre-emptive epidural analgesia effectively diminished pain levels and reduced the consumption of additional analgesics in the acute postoperative period among patients with pre-operative NLR ≥2 (12). Nevertheless, the existing literature offers limited insights into the association between epidural analgesia and postoperative NLR. Therefore, we undertook a retrospective analysis aimed at comparing NLR levels in patients administered epidural analgesia versus those receiving intravenous analgesia following thoracic surgery. This investigation seeks to elucidate the relationship between epidural analgesia and the inflammatory response subsequent to thoracic surgical procedures. The findings of our study may contribute to informing strategies for the management of postoperative analgesia in the context of thoracic surgeries. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2214/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of the Zhongshan Hospital (Xiamen Branch), Fudan University (No. B2025-017R). Due to the retrospective nature of the study, informed consent was waived.

Design and selection criteria

This retrospective study collected clinical data from 1,099 patients who underwent thoracic surgery from January 2020 to July 2024 at Xiamen Hospital, Zhongshan Hospital, Fudan University. The inclusion criteria encompassed adult patients (aged 18 years and older) who underwent thoracic surgery and utilized self-controlled analgesia in the postoperative period. The exclusion criteria comprised individuals with an American Society of Anesthesiologists (ASA) classification of IV, those undergoing emergency surgery, patients with preoperative analgesic use, chronic pain conditions, psychiatric disorders, or incomplete medical records. Patients were stratified into two groups based on the modality of postoperative analgesia: the patient-controlled epidural analgesia (PCEA) group and the patient-controlled intravenous analgesia (PCIA) group. The specific inclusion and exclusion processes are shown in Figure 1. It consisted of 10 experienced thoracic surgeons, anesthesiologists, and the surgical staff remained essentially unchanged during the study period.

Figure 1 Flowchart of patient selection. ASA, American Society of Anesthesiologists; PCEA, patient-controlled epidural analgesia; PCIA, patient-controlled intravenous analgesia.

In this study, all patients underwent surgery with a combination of general anesthesia and epidural anesthesia, followed by the implementation of self-controlled analgesia during the postoperative period. The PCEA regimen consisted of a solution containing 20 µg/mL hydromorphone and 0.12% ropivacaine, delivered as a 3–4 mL/h basal infusion with a 3 mL patient-controlled bolus dose and a 10-minute lockout interval. The PCIA group received a formulation containing 50 µg/mL hydromorphone and 0.04 mg/mL granisetron, delivered as a 1 mL/h basal infusion with a 3–4 mL patient-controlled bolus dose and a 10-minute lockout interval. These analgesic regimens represent our standard protocol, irrespective of the specific analgesic technique applied.

Data collection

In this study, all patients underwent a combination of general anesthesia and epidural anesthesia during surgery. Postoperative data were sourced from the hospital's electronic medical record system and a dedicated postoperative analgesic follow-up database. These sources provided comprehensive information on each patient, including demographic details, initial diagnosis, medical history (such as preoperative complications and cardiovascular-metabolic comorbidities), surgical specifics (including type and duration of surgery, intraoperative fluid management, and estimated blood loss), pathological findings, perioperative systemic inflammation scores, postoperative outcomes, pain profiles, and adverse events. The perioperative systemic inflammation score was assessed using the NLR, measured one day prior to surgery (D0) and two days postoperatively (POD2). Postoperative outcomes encompassed complications, timing of chest drain removal, length of hospital stay (LOS). Pain at rest and during movement on postoperative days 1 and 2 was evaluated utilizing the Numeric Rating Scale (NRS). Pain intensity was documented using a 10-centimeter NRS, in which a score of zero denoted the absence of pain and a score of ten represented the most severe pain imaginable. Adverse effects associated with postoperative analgesia were identified as hypotension, defined by a systolic blood pressure below 90 mmHg, as well as dizziness, headache, postoperative nausea and vomiting (PONV), and pruritus, all occurring within the initial 48 hours post-surgery.

Definitions

Individuals were classified as having hypertension if they exhibited a systolic blood pressure of ≥140 mmHg and/or a diastolic blood pressure of ≥90 mmHg, or if they were undergoing treatment with antihypertensive medication (13). The diagnostic criteria for diabetes in non-pregnant individuals include a fasting blood glucose (FPG) level of ≥126 mg/dL (≥7.0 mmol/L), measured after a minimum of 8 hours without caloric intake, or a 2-hour post-load glucose (2-h PG) level of ≥200 mg/dL (≥11.1 mmol/L) during an oral glucose tolerance test (OGTT). Additionally, in individuals presenting with classic symptoms of hyperglycemia or experiencing hyperglycemic crises, a random plasma glucose level of ≥200 mg/dL (≥11.1 mmol/L) is indicative of diabetes, where “random” refers to any time of day irrespective of the duration since the last meal (14). Hyperlipidemia is characterized by a total cholesterol level exceeding 200 mg/dL, triglycerides exceeding 150 mg/dL, high-density lipoprotein (HDL) levels below 40 mg/dL in males and below 50 mg/dL in females, and low-density lipoprotein (LDL) levels exceeding 130 mg/dL (15). Individuals diagnosed with one or more of the following conditions—coronary heart disease, stroke, hypertension, hyperlipidemia, and type 2 diabetes mellitus—are classified as having cardiometabolic diseases (CMDs) (16). Those diagnosed with two or more CMDs concurrently are identified as having cardiometabolic multimorbidity (CMM) (17).

Statistical analysis

All statistical analyses were conducted utilizing SPSS statistical software (Version 26.0, Chicago, IL, USA). Initially, the distribution of the data was evaluated through the application of the Shapiro-Wilk test for normality on continuous variables. Variables adhering to a normal distribution were represented as mean ± standard deviation (SD), with intergroup comparisons conducted using the independent samples t-test. Conversely, variables not adhering to a normal distribution were represented as median (quartiles), with intergroup comparisons conducted using the Mann-Whitney U test. Categorical variables were presented as frequencies (percentages), and intergroup comparisons were performed using either the chi-square test or Fisher’s exact test. To explore the multifactorial relationships between variables and the NLR, multiple linear regression models were employed, with regression coefficients (β), standard errors, and P values reported. All statistical tests were two-tailed, with statistical significance determined at P<0.05.

Results

During the study period, a total of 1,412 patients underwent thoracic surgery at Xiamen Hospital, Zhongshan Hospital, Fudan University. Following the application of exclusion criteria, 313 patients were omitted from the study: eight due to emergency surgery, two due to chronic pain conditions, and 303 due to incomplete clinical data and follow-up information. Consequently, 1,099 patients were included in the final analysis (Figure 1). Of the 1,099 recipients included, 533 in the PCEA group and 566 in the PCIA group. The demographic characteristics, including age, gender, body mass index (BMI), ASA classification, pathological results and CMM, were comparable between the two groups, as presented in Table 1.

The surgical parameters for the PCEA and PCIA groups are presented in Table 2. Surgical procedures were conducted in a similar manner across both groups (P=0.54), with no significant differences observed in blood loss, intraoperative rehydration, or urinary output during the surgery.

Preoperative NLR did not show statistically significant differences between the two groups (Table 3, Figure 2). However, the NLR at 48 hours postoperatively was significantly lower in the PCEA group (4.75) compared to the PCIA group (5.90) (P<0.001, Table 3). The NLR values at 48 hours postoperatively were found to be 2.78-fold and 3.52-fold higher in the PCEA and PCIA groups, respectively, in comparison to the preoperative values at 24 hours. The rate of increase in the NLR for the PCEA group was significantly lower than that of the PCIA group (P<0.001, Table 3).

Figure 2 Postoperative NLR and preoperative NLR. ***, P<0.001. NLR, neutrophil-to-lymphocyte ratio; PCEA, patient-controlled epidural analgesia; PCIA, patient-controlled intravenous analgesia.

In terms of postoperative pain management, the NRS pain score at rest on the first postoperative day was significantly lower in the PCEA group compared to the PCIA group (P<0.001, Figure 3A). Furthermore, the NRS scores during activity on both the first and second postoperative days were significantly reduced in the PCEA group relative to the PCIA group (P<0.001, Figure 3B) (Table 4).

Figure 3 NRS pain score. (A) Rest. (B) Movement. ***, P<0.001. NRS, Numeric Rating Scale; PCEA, patient-controlled epidural analgesia; PCIA, patient-controlled intravenous analgesia.

In contrast to the adverse reactions associated with postoperative analgesia, the incidence of pruritus was significantly higher in the PCEA group compared to the PCIA group (P=0.004). Conversely, the incidence of PONV was significantly higher in the PCIA group than in the PCEA group (P=0.002). Regarding hypotension, the incidence was slightly higher in the PCEA group compared to the PCIA group; however, this difference was not statistically significant. Additionally, the incidence of dizziness and headache was comparable between the two groups, with no statistically significant difference observed (Figure 4 and Table 5).

Figure 4 Adverse effects related to analgesia at 48 hours postoperatively. **, P<0.01. PCEA, patient-controlled epidural analgesia; PCIA, patient-controlled intravenous analgesia; PONV, postoperative nausea and vomiting.

In the context of postoperative complications, the incidence of postoperative infection (P=0.004) and lower extremity venous thrombosis (P=0.01) was significantly lower in the PCEA group compared to the PCIA group. Additionally, the incidence of pneumothorax, pleural effusion, subcutaneous emphysema, and anastomotic fistula was marginally lower in the PCEA group than in the PCIA group; however, these differences did not reach statistical significance (Figure 5 and Table 6).

Figure 5 Postoperative complications. *, P<0.05; **, P<0.01. DVT, deep vein thrombosis; PCEA, patient-controlled epidural analgesia; PCIA, patient-controlled intravenous analgesia.

Regarding postoperative recovery, the time to chest tube removal and LOS were significantly shorter in the PCEA group compared to the PCIA group [mean time (days): 4 vs. 5 and 9 vs. 11, respectively; P<0.001, P=0.005, Figure 6] (Table 4).

Figure 6 Chest tube removal time (A) and length of hospital stay (B) of PCIA and PCEA groups. **, P<0.01; ***, P<0.001. PCEA, patient-controlled epidural analgesia; PCIA, patient-controlled intravenous analgesia.

Discussion

Our retrospective study demonstrated that, in comparison to PCIA, epidural analgesia significantly reduces postoperative NLR values and mitigates the rate of postoperative NLR elevation in patients undergoing thoracic surgery. The occurrence of postoperative complications was reduced in the cohort receiving epidural analgesia compared to those receiving intravenous analgesia, and the duration of hospitalization was also shorter for the epidural analgesia group.

Thoracic surgeries (e.g., esophageal, pulmonary, and mediastinal procedures) are highly invasive and prolonged, exerting substantial physiological stress on patients. This stress impacts the circulatory and respiratory systems, triggering a pronounced systemic stress response. Consequently, neuroendocrine alterations occur, promoting the secretion of inflammatory factors and suppressing cellular immune function (18), which in turn increases the likelihood of postoperative complications. Thoracic epidural analgesia (TEA) has traditionally been regarded as the gold standard for postoperative analgesia in open thoracic surgery due to its precise analgesic effects (1). It has been demonstrated to enhance postoperative pulmonary function, decrease thromboembolic complications, reduce myocardial oxygen consumption, facilitate intestinal excretion, and expedite mobilization. Furthermore, TEA effectively diminishes the incidence of postoperative complications, including pulmonary atelectasis, hypoxemia, and pneumonia (19). Additionally, thoracic segmental epidural anesthesia has been shown to mitigate stress-induced immunosuppression in surgical patients (20). Our study encompassed patients who underwent thoracic procedures, such as lung, esophageal, and mediastinal surgeries. The study demonstrated that the analgesic effect was superior in the PCEA group compared to the PCIA group. The times to chest tube removal and LOS were significantly shorter in the PCEA group than in the PCIA group [mean time (days): 4 vs. 5 and 9 vs. 11, respectively; P<0.01, Figure 6, Table 4]. The decision to remove a chest tube is deemed appropriate under the following conditions (21): (I) absence of an air leak, indicated by the tube being on a water seal; (II) a 24-hour drainage volume of ≤450 mL of non-bloody, non-chylous fluid; (III) the patient demonstrates clinical stability, rendering routine post-removal radiographs unnecessary. Postoperative pain associated with thoracoscopic surgery predominantly originates from chest drains, with the majority of patients having their chest tubes removed on postoperative days 3 to 4 (22). In our study, the mean duration for chest tube removal was 3 days in the PCEA group and 4 days in the PCIA group. Postoperative analgesia was generally administered for 3 days, with epidural analgesia typically discontinued following chest tube removal. Given the retrospective nature and inherent limitations of this study, further prospective research is warranted to elucidate the relationship between chest tube removal and analgesia. Moreover, the enhanced analgesic effect facilitated superior pain management, thereby contributing to a reduced LOS.

The concept of the NLR, initially introduced by Zahorec in 2001, serves as a biomarker calculated by dividing the neutrophil count by the lymphocyte count in routine blood tests. It is a simple, cost-effective, and widely accessible indicator of inflammation, immune status, and disease severity (23). Cellular immunity plays a crucial role in the body’s anti-tumor immune response, and an elevated NLR reflects the body’s inflammatory process, which has been shown to correlate with poor tumor outcomes (24). During surgical anesthesia, the neuroendocrine system becomes activated, the immune system undergoes alterations, systemic leukocytes are modified, and the NLR is influenced by both the surgical procedure and the type of anesthesia employed (25). Postoperative pain exacerbates the inflammatory state, elevates stress levels, and contributes to immunosuppression, thereby diminishing patient comfort and hindering early postoperative mobilization and recovery of gastrointestinal function, which are critical factors in postoperative recovery (26).

The normal NLR varies among different populations, ranging from 1.65±0.79 to 2.8±1.6 (20). In our study, the preoperative NLR was 1.72 in the PECA group and 1.70 in the PCIA group, with no statistically significant difference observed between the two groups. Previous research has demonstrated that epidural blockade functions by inhibiting afferent responses to noxious stimuli, effectively blocking sympathetic nerves, reducing surgically induced stress and inflammation, safeguarding the patient’s innate immune system, and facilitating postoperative recovery (27). However, the relationship between the mode of postoperative analgesia and the patient’s NLR has been less extensively explored in the literature, and currently, there is insufficient data available on this topic.

In addition to surgical trauma, NLR is influenced by the mode of anesthesia (25). The neuroendocrine changes induced by different anesthetic techniques may have an impact on NLR, although these effects remain unclear. In a prospective study, Surhonne et al. examined the impact of anesthesia modality on NLR in patients undergoing infraumbilical surgery and found that spinal anesthesia significantly reduced NLR compared to general anesthesia (20). These findings align with our results, which indicate that the postoperative NLR in patients receiving postoperative epidural analgesia was 4.75, lower than that observed in the PCIA group, which was 5.90. In the postoperative period, the NLR values at 48 hours increased by 2.78-fold and 3.52-fold in the PCEA and PCIA groups, respectively, compared to the 24-hour preoperative period. Notably, the rate of increase in the PCEA group was significantly lower than that observed in the PCIA group. Our study indicates that TEA effectively reduced NLR postoperatively. Furthermore, we identified a positive correlation between age and NLR values, corroborating the findings of Huguet et al. (28). Additionally, we observed that a higher frequency of PCA.

Sessions within 48 hours is associated with an increase in NLR, potentially due to the activation of the neuroendocrine stress response resulting from inadequate analgesia. A prospective observational cohort study by another group demonstrated that variations in NLR were linked to chronic postoperative pain (29). Similarly, research by Surhonne et al. found that the use of epidural analgesia during labor attenuated the maternal inflammatory response and established a correlation between NLR values and pain levels (20). Consequently, epidural analgesia may be employed to mitigate postoperative pain and reduce the inflammatory response in elderly patients and those exhibiting elevated preoperative NLR.

There are several limitations in this study. It is a retrospective analysis rather than a randomized controlled trial, and the data were sourced from a single institution. As a result, the potential for confounding due to unmeasured variables cannot be entirely ruled out, which may introduce bias into the findings. Furthermore, since most patients only undergo laboratory tests before surgery and on the second day after surgery, acute pain service (APS) only conducts follow-up visits on the second day after surgery. Therefore, the endpoint of this study is limited to the short-term changes in postoperative inflammatory markers (NLR). Regarding the time point at which the NLR returns to normal in both groups and the point at which the differences in pain scores during hospitalization are no longer statistically significant, a prospective study may be needed for further analysis.

Conclusions

In conclusion, the administration of postoperative epidural analgesia significantly reduces the postoperative NLR and contributes valuable insights into the optimization of postoperative analgesic regimens for patients undergoing thoracic surgery.

Acknowledgments

We would like to express our gratitude to the team members for their contributions to this article, and then we will work diligently to do relevant research in the future.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2214/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2214/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2214/prf

Funding: The study was supported by the Xiamen Healthcare Guidance Research Funding (grant No. 3502Z20214ZD1063), Shanghai Municipal Health Commission (grant No. 202240294), National Natural Science Foundation of China (grant No. 81801376), and Fujian Provincial Natural Science Foundation of China (grant No. 2025D011).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2214/coif). The authors have no 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. This study was approved by the Ethics Committee of the Zhongshan Hospital (Xiamen Branch), Fudan University (No. B2025-017R). Due to the retrospective nature of the study, informed consent was waived.

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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