The impact of ulinastatin on postoperative clinical outcomes in patients with gastric cancer: a retrospective cohort analysis

Introduction

Gastric cancer (GC) remains a major global public health burden, characterized by high incidence, substantial mortality, and poor long-term survival. According to the most recent estimates from the International Agency for Research on Cancer (IARC), GC ranks fifth in global cancer incidence and third in cancer-related mortality worldwide, with a particularly high disease burden in East Asia, especially China (1,2). Surgical resection remains the cornerstone of curative treatment for GC, often combined with perioperative systemic therapies depending on tumor stage.

With advances in minimally invasive techniques, laparoscopic gastrectomy has been increasingly adopted in the management of GC and is associated with reduced surgical trauma, faster postoperative recovery, and shorter hospital stay compared with open surgery (3). Nevertheless, laparoscopic GC surgery is technically demanding and typically requires prolonged operative time and sustained carbon dioxide pneumoperitoneum, exposing patients to a series of unique perioperative physiological stresses.

The establishment of carbon dioxide pneumoperitoneum leads to increased intra-abdominal pressure, impaired venous return, reduced cardiac output, and decreased pulmonary compliance (4). These hemodynamic and respiratory alterations can compromise visceral organ perfusion and microcirculatory flow, predisposing tissues to ischemic injury. Upon desufflation, the restoration of blood flow triggers ischemia-reperfusion injury, characterized by excessive generation of reactive oxygen species, activation of inflammatory cascades, endothelial dysfunction, and subsequent organ injury (5-8). Collectively, these processes contribute to an exaggerated systemic inflammatory response during the perioperative period of laparoscopic gastrectomy.

Accumulating evidence suggests that excessive perioperative inflammation is not merely a transient biochemical phenomenon but has important clinical implications. Heightened inflammatory responses have been associated with delayed gastrointestinal recovery, increased risk of postoperative infections, impaired wound healing, and a higher incidence of severe complications such as anastomotic leakage (9). Moreover, perioperative inflammatory status may influence postoperative immune function and tumor immune surveillance, potentially affecting long-term oncological outcomes.

Currently, several perioperative strategies have been implemented to mitigate surgical stress and inflammation in GC surgery, including restrictive fluid management, lung-protective ventilation strategies, and enhanced recovery after surgery (ERAS) protocols (10,11). While these measures have improved postoperative recovery to some extent, they are insufficient to fully suppress surgery-induced systemic inflammation (10). Pharmacological anti-inflammatory interventions, therefore, remain an area of active interest. However, commonly used agents such as corticosteroids and nonsteroidal anti-inflammatory drugs may increase the risk of immunosuppression, bleeding, and impaired wound healing, limiting their routine use in oncologic surgery (12,13).

Ulinastatin (UTI) is a non-specific protease inhibitor isolated from human urine and belongs to the family of endogenous glycoproteins with well-established anti-inflammatory and organ-protective properties. Mechanistically, UTI inhibits the release of pro-inflammatory cytokines, suppresses neutrophil activation and adhesion, attenuates oxidative stress, and improves microcirculatory perfusion (14,15). Clinically, perioperative administration of UTI has been shown to reduce postoperative inflammatory markers in patients undergoing thoracoscopic lung cancer surgery (16) and laparoscopic colorectal cancer resection (17), with potential benefits in immune modulation and short-term recovery (18). Meta-analyses of randomized controlled trials further suggest that UTI can effectively attenuate perioperative inflammatory responses and may reduce inflammation-related postoperative complications (19).

Despite these encouraging findings, evidence regarding the clinical effectiveness of UTI in patients undergoing laparoscopic gastrectomy for GC remains limited. In particular, whether intraoperative UTI administration can meaningfully modulate postoperative inflammatory responses and translate into improved clinical recovery or reduced organ dysfunction in this population has not been adequately investigated.

Therefore, the present retrospective cohort study aimed to evaluate the association between intraoperative UTI administration and postoperative inflammatory responses, liver function changes, and clinical recovery outcomes in patients undergoing laparoscopic gastrectomy for GC. By applying propensity score–based adjustment and longitudinal statistical modeling, this study sought to provide clinically relevant evidence regarding the potential role of UTI in perioperative management of GC surgery. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-671/rc).

Methods

Study design and participants

This retrospective observational cohort study was conducted at The Sixth Affiliated Hospital of Sun Yat-sen University. Consecutive adult patients who underwent elective laparoscopic gastrectomy and were pathologically diagnosed with GC between January 2021 and January 2023 were screened for eligibility through the institutional electronic medical record system. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Medical Ethics Committee of The Sixth Affiliated Hospital of Sun Yat-sen University (No. 2025ZSLYEC-696). Informed consent for this retrospective study was waived.

Inclusion criteria were as follows:

• Age ≥18 years;
• Pathologically confirmed primary gastric adenocarcinoma;
• Laparoscopic gastrectomy performed under general anesthesia.

Exclusion criteria were:

• Receipt of preoperative neoadjuvant chemotherapy or radiotherapy;
• Presence of other concurrent malignant tumors;
• Remnant GC;
• Documented preoperative infection or receipt of systemic antibiotic therapy within 7 days before surgery.

A flowchart detailing patient selection is provided in Figure 1.

Figure 1 Flow diagram of the study parameters. PSM, propensity score matching.

Decision-making process for UTI administration

The decision to administer UTI intraoperatively was made by the attending anesthesiologist and surgeons based on overall perioperative risk assessment, including anticipated surgical stress, tumor burden, baseline inflammatory status. To mitigate this inherent limitation of the observational design, propensity score-based methods were prespecified and implemented, as detailed in the statistical analysis section.

All patients received standardized general anesthesia according to institutional protocols. In the UTI group, based on the standard anesthesia regimen, UTI 300,000 units was diluted in 100 mL of normal saline and administered intravenously intraoperatively. Patients in the Control group did not receive UTI.

Data sources and variables

Demographic, clinical, and perioperative data were extracted from the electronic medical record system. Baseline variables included age, sex, body mass index (BMI), history of hypertension, history of diabetes mellitus, and tumor-node-metastasis (TNM) stage.

Perioperative laboratory parameters included inflammatory markers—C-reactive protein (CRP), white blood cell count (WBC), and neutrophil count (NEUT)—and liver function indices—aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (Tbil). These parameters were routinely measured at three predefined time points: within 24 hours before surgery (baseline), postoperative day 1 (approximately 24 h), and postoperative day 3 (approximately 72 h).

Laboratory measurements

All laboratory tests were performed by the Department of Laboratory Medicine of The Sixth Affiliated Hospital of Sun Yat-sen University using standardized automated analyzers and quality-controlled procedures. CRP concentrations were measured using an immunoturbidimetric assay. Complete blood counts, including WBC and NEUT, were obtained using automated hematology analyzers. Liver function indices, including AST and ALT, were measured using enzymatic methods, while Tbil was determined by the diazo method.

Propensity score matching (PSM)

To reduce baseline imbalance and confounding by indication associated with non-randomized UTI administration, PSM was performed. Propensity scores were estimated using a logistic regression model including age, sex, BMI category, hypertension, diabetes, TNM stage, and baseline laboratory values (CRP, WBC, and NEUT). A 1:1 nearest-neighbor matching without replacement was conducted using a caliper width of 0.1 of the standard deviation of the logit of the propensity score. Balance between groups before and after matching was assessed using standardized mean differences and conventional statistical tests.

Outcomes

The primary outcomes were postoperative inflammatory responses, assessed by changes in CRP, WBC, and NEUT from baseline on postoperative day 1 and day 3.

The secondary outcomes included postoperative liver function changes (AST, ALT, and Tbil) and postoperative hospital length of stay.

Postoperative hospital length of stay was defined as the number of days from the date of surgery to the date of hospital discharge. Discharge decisions followed standardized institutional criteria, including adequate pain control, tolerance of oral intake, absence of major postoperative complications requiring inpatient management, and stable laboratory parameters.

Longitudinal outcome analysis

For repeated postoperative laboratory measurements, linear mixed-effects models were used to evaluate changes over time and to account for within-subject correlations. Fixed effects included treatment group (UTI vs. Control), time point (postoperative day 1 and day 3), and their interaction, with adjustment for baseline values of the corresponding outcome variable. Additionally, to rigorously adjust for residual confounding, we included potential confounders (age, sex, BMI, hypertension, and diabetes) as well as the baseline values of the corresponding outcome variable as fixed effects in the model.

Analysis of postoperative hospital stay

Multivariable linear regression analysis was performed to identify factors associated with postoperative hospital length of stay. Covariates included age, sex, BMI category, hypertension, diabetes, TNM stage, and UTI administration.

Statistical analysis

Considering the limited sample size in the UTI group, we avoided listwise deletion. Instead, missing values were handled using multiple imputation methods to preserve statistical power and reduce bias.

Continuous variables were expressed as mean ± standard deviation or median with interquartile range, depending on distribution. Categorical variables were presented as frequencies and percentages. Normality was assessed using the Shapiro-Wilk test, and homogeneity of variance was evaluated using Levene’s test. Between-group comparisons were performed using independent-sample t-tests or Mann-Whitney U tests for continuous variables and chi-square tests or Fisher’s exact tests for categorical variables, as appropriate.

Results

Baseline characteristics

Baseline characteristics before PSM

According to the predefined inclusion and exclusion criteria, a total of 415 patients were included in the analysis, comprising 53 patients in the UTI group and 362 patients in the Control group prior to PSM.

As shown in Table 1, there were no statistically significant differences between the UTI and Control groups in major demographic and clinical characteristics, including age, sex, BMI categories, history of hypertension, history of diabetes, and TNM tumor stage (all P>0.05).

Regarding preoperative laboratory parameters, baseline serum CRP, WBC, and liver function indices (AST, ALT, and Tbil) were comparable between the two groups and within normal reference ranges (all P>0.05). However, the baseline neutrophil count (NEUT) was modestly but significantly higher in the UTI group compared with the Control group [(4.40±3.18) ×10⁹/L vs. (3.61±1.64) ×10⁹/L, P=0.01].

Baseline characteristics after PSM

After 1:1 PSM, a total of 100 patients were included in the matched cohort (50 per group). As shown in Table 2, the UTI and Control groups were well balanced with respect to age, sex, hypertension, diabetes, TNM stage, and preoperative laboratory parameters, including CRP, WBC, NEUT, and liver function indices (all P>0.05). After matching, a statistically significant difference in BMI distribution remained (P=0.01), with a slightly higher proportion of patients in the UTI group having a BMI of 18.5–24 kg/m².

Clinical outcomes

Primary outcomes: postoperative inflammatory markers

Both the UTI and Control groups exhibited marked postoperative inflammatory responses. Serum CRP, WBC, and NEUT increased significantly at 24 hours after surgery. WBC and NEUT reached their peak levels at postoperative day 1. By postoperative day 3, WBC and NEUT levels declined in both groups, approaching baseline values, whereas CRP remained elevated compared with postoperative day 1 (Figure 2).

Figure 2 The effect of UTI on the clinical outcome of patients undergoing laparoscopic gastrectomy. (A) CRP; (B) WBC; (C) NEUT; (D) AST; (E) ALT; (F) Tbil. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; NEUT, neutrophil count; Post-op day 1, day 1 post-surgery; Post-op day 3, day 3 post-surgery; Pre-op, preoperative baseline; Tbil, total bilirubin; UTI, ulinastatin; WBC, white blood cell.

Linear mixed-effects models for repeated measures were applied to evaluate longitudinal changes and account for within-subject correlations, adjusting for baseline values. At postoperative day 3, the estimated mean increase in CRP from baseline was significantly lower in the UTI group compared with the Control group (91.79±15.64 vs. 114.68±19.04 mg/L; mean difference −22.88±24.64 mg/L; P=0.04). For NEUT, the increase from baseline at postoperative day 3 was slightly lower in the UTI group than in the Control group [(2.77±1.02) ×10⁹/L vs. (3.07±0.95) ×10⁹/L; mean difference (−0.30±1.34) ×10⁹/L; P=0.66], but this difference did not reach statistical significance. WBC trajectories were similar between the two groups, with no significant group × time interaction observed (P>0.05) (Table 3).

Secondary observed outcomes

Liver function indices

Postoperative liver function markers (AST, ALT, and Tbil) increased significantly at 24 hours after surgery in both groups, with AST elevations more pronounced than ALT. By postoperative day 3, AST, ALT, and Tbil decreased substantially in both groups, returning near preoperative levels (Figure 2, Table 3).

Linear mixed-effects model analyses indicated no significant group × time interaction for AST or Tbil (P>0.05). However, the ALT increase from baseline at postoperative day 3 was significantly lower in the UTI group compared with the Control group (2.89±5.60 vs. 23.12±14.13 U/L; mean difference −20.22±15.20 U/L; P=0.01).

Postoperative hospital length of stay

Multivariable linear regression was performed to identify factors associated with postoperative hospital length of stay (Table 4). The results showed UTI administration was not independently associated with postoperative hospital stay [β=0.35, 95% confidence interval (CI): −3.33 to 4.02; P=0.48].

Importantly, a history of diabetes was identified as an independent risk factor for prolonged postoperative hospital stay (β=3.35, 95% CI: 1.67 to 4.98; P=0.03), indicating a clinically meaningful increase in hospitalization duration among diabetic patients. No significant associations were observed for age, sex, BMI categories, hypertension, or TNM stage (all P>0.05).

Discussion

Laparoscopic gastrectomy is a standard minimally invasive approach for GC, offering advantages such as reduced surgical trauma and faster early recovery compared with open surgery (3). Nevertheless, even laparoscopic procedures elicit significant perioperative inflammatory responses, as evidenced in both UTI and Control groups by marked elevations in CRP, WBC, and NEUT at 24 hours postoperatively. These observations are consistent with previous reports showing that minimally invasive surgery can still trigger substantial cytokine release, potentially affecting postoperative recovery in GC patients (20,21).

Our study demonstrated that intraoperative UTI administration significantly attenuated CRP elevation at postoperative day 3, confirming a biochemical anti-inflammatory effect. This aligns with prior studies in other surgical settings, including pancreatobiliary, colorectal, and thoracic surgeries, where UTI inhibited neutrophil activation and cytokine release, reduced oxidative stress, and improved short-term recovery (16,22-24). The observed reduction in CRP may indicate that UTI modulates the systemic inflammatory response, potentially mitigating inflammation-related tissue injury (14,15). Recent evidence further suggests that pharmacological anti-inflammatory interventions like UTI may influence perioperative immunometabolic pathways, reducing pro-inflammatory cytokine surges and attenuating organ stress during complex abdominal surgery (25).

However, the attenuation of CRP did not translate into significant differences in WBC, NEUT, or postoperative hospital length of stay between groups. This underscores an important clinical consideration: biochemical improvements do not necessarily correspond to immediate functional or recovery benefits. The lack of effect on hospital stay may be due to the single intraoperative dose of UTI, which might be insufficient to influence complex clinical endpoints influenced by multiple factors such as comorbidities, surgical complexity, and institutional discharge practices (26). Furthermore, recent studies indicate that perioperative inflammation interacts with endothelial and microvascular function, suggesting that isolated biochemical modulation may not fully capture clinical recovery outcomes (27).

Interestingly, diabetes emerged as an independent predictor of prolonged postoperative hospitalization, consistent with previous reports linking hyperglycemia and impaired wound healing to delayed recovery (28,29). This emphasizes that perioperative recovery is multifactorial, and pharmacological attenuation of inflammation may complement—but not replace—optimized metabolic, anesthetic, and surgical management strategies. Additional research highlights the role of inflammation-mediated immune modulation in postoperative complications, supporting the integration of anti-inflammatory strategies within comprehensive perioperative care (30).

Regarding liver function, postoperative ALT elevations at day 3 were lower in the UTI group, whereas AST and Tbil were not significantly different. This suggests a partial hepatoprotective effect of UTI, but individual patient factors such as pre-existing liver disease, intraoperative blood loss, and transfusions likely influence postoperative liver function more broadly (31). Recent findings also point to the potential protective effects of protease inhibitors on hepatic microcirculation and oxidative stress after major abdominal surgery (32).

There are certain limitations in this study. First, as a single-center, retrospective observational study, residual confounding cannot be fully excluded despite PSM. Unmeasured factors such as intraoperative hemodynamics, anesthetic depth, and surgeon variability could have influenced both inflammatory markers and recovery outcomes. Second, the study used a single standardized UTI dose without weight-based or repeated administration, potentially limiting the magnitude of observable clinical benefits. Third, postoperative outcomes such as hospital length of stay are influenced by multiple non-inflammatory factors, including institutional discharge criteria and perioperative care protocols. Consequently, while the biochemical anti-inflammatory effect of UTI is evident, its translation into meaningful clinical outcomes remains uncertain.

Future investigations should consider prospective randomized studies with multi-dose UTI protocols to determine whether enhanced perioperative anti-inflammatory modulation can lead to measurable improvements in clinical recovery. Integration of UTI within ERAS pathways may provide synergistic benefits by combining pharmacological suppression of inflammation with optimized fluid management, early mobilization, and lung-protective ventilation.

Conclusions

Intraoperative administration of UTI reduces postoperative CRP elevation in patients undergoing laparoscopic gastrectomy, demonstrating a clear anti-inflammatory effect. However, WBC, NEUT, and hospital length of stay were not significantly affected, suggesting limited impact on short-term clinical recovery. Integration of UTI with comprehensive perioperative management may be necessary to achieve meaningful clinical benefits.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-671/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-671/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-671/prf

Funding: This study was supported by the Medical Scientific Research Foundation of Guangdong Province, China (No. A202202).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-671/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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Medical Ethics Committee of The Sixth Affiliated Hospital of Sun Yat-sen University (No. 2025ZSLYEC-696). Informed consent for this retrospective study 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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