Effect of Ulinastatin on the Inflammatory Response After Video-Assisted Thoracic Lobectomy in Patients With Lung Cancer: A Randomized Controlled Study
Lung cancer remains the leading cause of cancer death globally, and surgical resection—like video-assisted thoracic lobectomy (VATS)—is the gold standard for curing early-stage disease. But a critical part of this surgery—one-lung ventilation (OLV), where only one lung is used for breathing—poses a hidden risk: inflammation that damages lungs, suppresses immunity, and threatens recovery. Now, a 2022 study from Seoul St. Mary’s Hospital explores whether ulinastatin, a drug used to reduce surgical inflammation, can protect lung cancer patients during these procedures.
Why Inflammation Matters for Lung Cancer Surgery
During OLV, the ventilated lung is overstretched by non-physiological tidal volumes and flooded with blood (hyperperfusion), while the collapsed lung is injured by surgical manipulation and re-expansion. Both processes trigger immune cells (like neutrophils) to release inflammatory cytokines—chemical messengers that spread damage to both lungs and suppress the immune system. For cancer patients, this is doubly dangerous: a weakened immune response can let residual cancer cells grow or spread (metastasize).
Surgery and anesthesia also shift the balance of T helper (Th) cells—key players in immunity. Th1 cells secrete interferon-gamma (IFN-γ), which activates cancer-killing cells (like cytotoxic T cells and natural killer cells). Th2 cells make interleukin-4 (IL-4), which drives antibody production but suppresses Th1 activity. Surgical stress pushes this balance toward Th2, leaving patients vulnerable to infection and recurrence—a problem previous research in the Surgery journal has highlighted.
What Is Ulinastatin?
Ulinastatin is a urinary trypsin inhibitor—a glycoprotein extracted from human urine that blocks enzymes (like neutrophil elastase) and free radicals linked to inflammation and organ damage. It’s already used in surgery to improve microcirculation (blood flow to tissues) and reduce complications from shock or massive bleeding. But its effect on the immune balance of lung cancer patients undergoing OLV was untested—until this study.
The Study: Design and Methods
Won Jung Hwang, Min A. Joo, and Jin Joo—anesthesiologists at The Catholic University of Korea’s Seoul St. Mary’s Hospital—conducted a randomized controlled trial (RCT) with 26 patients (13 in each group) undergoing VATS for stage I lung cancer between May and August 2020.
Key inclusion criteria: Patients aged 19–70 with no history of heart disease, asthma, COPD, or liver problems. Exclusions included sensitivity to anesthesia drugs (e.g., propofol) or prior cancer treatments.
Intervention
- Ulinastatin group: 300,000 units of ulinastatin mixed with 100 mL saline, given over 1 hour after anesthesia induction.
- Control group: 100 mL saline (a placebo) given the same way.
All patients received standardized anesthesia to minimize variables:
- Target-controlled infusions of propofol (sedation) and remifentanil (pain relief).
- Protective ventilation: Small tidal volumes (4–5 mL/kg predicted body weight) and positive end-expiratory pressure (PEEP, 5–10 cmH₂O) to reduce lung injury.
- Paravertebral block (a nerve block) for pain control, which lowers inflammation by reducing stress hormones.
- Carbohydrate drink 2 hours before surgery to blunt the stress response.
Key Findings: Ulinastatin Boosts Immune Balance
The team measured IFN-γ (Th1 marker) and IL-4 (Th2 marker) in blood samples taken at three times:
- T0: Right after anesthesia induction (baseline).
- T1: 2 hours after induction.
- T2: 30 minutes after arriving in the recovery room.
The results were clear:
- Baseline balance: Both groups had nearly identical IFN-γ/IL-4 ratios (≈6,900), meaning their Th1/Th2 balance was similar before surgery.
- Post-surgery shift: By T2 (recovery), the ulinastatin group’s IFN-γ/IL-4 ratio was 3x higher than the control group (20,148 vs. 6,674). This meant ulinastatin preserved a Th1-dominant immune response—critical for fighting cancer.
- Cytokine changes: IFN-γ levels were significantly higher in the ulinastatin group at T2 (5.5 pg/mL vs. 2.4 pg/mL in controls). IL-4 trended lower in the ulinastatin group but wasn’t statistically different.
In short: Ulinastatin prevented the surgery-induced shift from Th1 (cancer-fighting) to Th2 (antibody-focused) immunity.
What This Means for Patients and Doctors
The study’s biggest takeaway is that ulinastatin regulates the immune response during lung cancer surgery. By boosting IFN-γ and the Th1/Th2 ratio, it may:
- Reduce inflammation-related lung damage (like acute lung injury).
- Preserve the body’s ability to kill residual cancer cells.
- Lower risks of infection or recurrence—though long-term data is needed to confirm this.
The team also noted that their protective anesthesia protocol (small tidal volumes, paravertebral blocks, pre-op carbs) likely enhanced ulinastatin’s effect by minimizing baseline stress. This aligns with research showing that “enhanced recovery after surgery (ERAS)” protocols improve outcomes for cancer patients.
Limitations to Consider
Like all early studies, this RCT has caveats:
- Small sample size: Only 26 patients were included (13 per group). Larger trials are needed to confirm results.
- Short follow-up: Immune changes were measured only 30 minutes post-recovery. The peak of surgical immunosuppression happens 3 days after surgery—so long-term data on recurrence or metastasis is missing.
- No clinical outcomes: The study focused on cytokines, not real-world results like pneumonia, hospital stay length, or survival.
Conclusion: A Promising Step for Immune Protection
This study is the first to link ulinastatin to preserving the Th1/Th2 balance in lung cancer patients undergoing VATS. The results suggest ulinastatin could become a standard part of anesthesia for these surgeries—helping patients recover faster and maintain immunity against cancer recurrence.
The researchers plan to expand their work with larger, longer trials to measure ulinastatin’s effect on clinical outcomes like metastasis. For now, their findings offer hope: a simple drug may help lung cancer patients not just survive surgery—but thrive afterward.
Study Details
- Authors: Won Jung Hwang, Min A. Joo, Jin Joo (Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea).
- Journal: Chinese Medical Journal (2022, Volume 135, Issue 7).
- Trial Registration: Clinical Research Information Service (CRIS) of Korea—KCT0005533.
- Ethics Approval: Seoul St. Mary’s Hospital Institutional Review Board (KC19MESI0364).
- Funding: Catholic Medical Center Research (5-2018-B0001-00004).
doi.org/10.1097/CM9.0000000000001937
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