Effect of Ulinastatin on the Inflammatory Response After Video-Assisted Thoracic Lobectomy in Patients with Lung Cancer: A Randomized Controlled Study
Lung cancer remains one of the most prevalent and deadly cancers worldwide, with surgical resection being the first-line treatment for eligible patients. Video-assisted thoracic surgery (VATS) has become a widely adopted approach due to its minimally invasive nature and reduced postoperative complications. However, one-lung ventilation (OLV), a standard anesthetic technique during lung surgery, can induce inflammatory responses that contribute to local and systemic lung damage. This study aimed to evaluate the effect of ulinastatin, a urinary trypsin inhibitor (UTI), on the inflammatory response after VATS lobectomy in patients with lung cancer.
Background and Rationale
Surgical resection is the primary treatment for lung cancer, and OLV is essential for facilitating the procedure. However, OLV can lead to complications such as acute lung injury (ALI), which occurs in 4% to 15% of patients and is a leading cause of postoperative mortality. The ventilated lung is exposed to high tension, oxidative stress, and capillary shear stress, while the non-ventilated lung undergoes ischemia-reperfusion injury upon re-expansion. These processes trigger the release of inflammatory cytokines, promoting local and contralateral lung damage through systemic circulation.
The immune response is mediated by T helper (Th) cells, which differentiate into Th1 and Th2 subsets. Th1 cells produce interferon-gamma (IFN-γ), which activates cell-mediated immunity, while Th2 cells secrete interleukin-4 (IL-4) and IL-10, promoting humoral immunity. Surgery and anesthesia suppress cell-mediated immunity by reducing the Th1/Th2 ratio, potentially increasing susceptibility to infections and cancer recurrence.
Ulinastatin, a nonspecific protease inhibitor extracted from human urine, has anti-inflammatory and anti-metastatic properties. It inhibits lysosomal enzymes and free radical production, reducing systemic inflammatory responses and organ injury. Despite its widespread use in managing surgical stress, limited research has explored its effects on the inflammatory response after lung cancer surgery. This study sought to address this gap by investigating the impact of ulinastatin on IFN-γ and IL-4 levels and the IFN-γ/IL-4 ratio in patients undergoing VATS lobectomy.
Methods
Study Design and Participants
This randomized, prospective study enrolled adult patients aged 19 to 70 years scheduled for VATS lobectomy to treat lung cancer between May 2020 and August 2020. Patients with stage I lung cancer, confirmed by preoperative computed tomography, and no significant medical history other than hypertension or diabetes mellitus were included. Exclusion criteria included myocardial infarction, coronary artery disease, chronic lung diseases, elevated liver enzymes, and hypersensitivity to anesthetics.
Randomization and Intervention
Patients were randomized into the ulinastatin (U) or control (C) group using block randomization. An anesthesiologist not involved in patient care prepared the study solutions, ensuring blinding. The ulinastatin group received 300,000 units of UTI mixed with 100 mL of normal saline, while the control group received 100 mL of normal saline. The solutions were administered over 1 hour after anesthesia induction.
Anesthesia and Surgical Procedures
Patients fasted for 8 hours before surgery but consumed 200 mL of a carbohydrate drink 2 hours prior. Standard monitoring included electrocardiogram, non-invasive blood pressure, pulse oximetry, and bispectral index (BIS). Anesthesia was induced with propofol, remifentanil, and rocuronium and maintained with propofol, remifentanil, and oxygen/air. A paravertebral block at the T2–3 level was performed for postoperative pain control. Protective ventilation during OLV included a tidal volume of 4–5 mL/kg of predicted body weight and positive end-expiratory pressure (PEEP) of 5–10 cmH2O.
Outcome Measures
Blood samples were collected at three time points: immediately after anesthesia induction (T0), 2 hours after induction (T1), and 30 minutes after entering the recovery room (T2). Serum levels of IFN-γ and IL-4 were measured using enzyme-linked immunosorbent assay (ELISA) kits. The IFN-γ/IL-4 ratio was calculated to assess the Th1/Th2 balance.
Statistical Analysis
Sample size calculation was based on a previous study, with 14 patients per group required to achieve 80% power. Data were analyzed using SPSS software. Repeated-measures ANOVA was used to compare cytokine levels between groups, with Bonferroni correction for multiple comparisons. A p-value < 0.05 was considered significant.
Results
Patient Characteristics
Twenty-eight patients were enrolled, with 14 randomized to each group. Two patients were excluded due to conversion to open thoracotomy and loss to follow-up. Demographic and perioperative data, including age, gender, surgery time, and blood loss, were comparable between groups (Table 1).
Inflammatory Outcomes
At baseline (T0), IFN-γ and IL-4 levels and the IFN-γ/IL-4 ratio did not differ between groups. IFN-γ levels remained stable at T1 in both groups but were significantly higher in the ulinastatin group at T2 (5.5 ± 2.0 pg/mL vs. 2.4 ± 0.5 pg/mL, p < 0.017). IL-4 levels showed no significant differences between groups at any time point. The IFN-γ/IL-4 ratio was significantly higher in the ulinastatin group at T2 (20,148.2 ± 5054.3 vs. 6674.0 ± 2963.6, p < 0.017) (Figures 2–4).
Discussion
This study demonstrated that ulinastatin administration during VATS lobectomy increased IFN-γ levels and the IFN-γ/IL-4 ratio, suggesting a preservation of the Th1/Th2 balance. These findings indicate that ulinastatin may attenuate the immunosuppressive effects of surgery and anesthesia, potentially reducing postoperative complications and cancer recurrence.
Surgical stress and anesthesia suppress the immune system by activating the hypothalamus-pituitary-adrenal axis and inhibiting immune cell function. OLV exacerbates this response by inducing lung injury and ischemia-reperfusion damage. Ulinastatin, by inhibiting inflammatory cytokines and proteases, may mitigate these effects. Previous studies have shown that ulinastatin reduces systemic inflammation and organ injury, supporting its role in enhancing postoperative recovery.
The observed increase in the IFN-γ/IL-4 ratio aligns with the known immunomodulatory effects of ulinastatin. A higher Th1/Th2 ratio is associated with enhanced cell-mediated immunity, which is crucial for preventing infections and cancer metastasis. The study’s findings suggest that ulinastatin may help maintain immune homeostasis during the perioperative period, offering clinical benefits beyond its anti-inflammatory properties.
Limitations
This study has several limitations. First, the follow-up period was short, and the study did not assess long-term clinical outcomes such as cancer recurrence or metastasis. Second, the sample size was relatively small, limiting the generalizability of the results. Future studies with larger cohorts and extended follow-up are needed to validate these findings and explore the clinical implications of ulinastatin administration.
Conclusion
Ulinastatin administration during VATS lobectomy attenuated the anti-inflammatory response by increasing IFN-γ levels and the IFN-γ/IL-4 ratio. These results suggest that ulinastatin may play a protective role in preserving immune balance and reducing postoperative complications in lung cancer patients. Further research is warranted to evaluate the long-term effects of ulinastatin on clinical outcomes, including cancer recurrence and survival.
doi.org/10.1097/CM9.0000000000001937
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