Abstract
Background
Postoperative complications of gastrectomy severely impact patient prognosis and impose a substantial economic burden. This study aims to assess the effect of adding omega-3 fish oil emulsion to parenteral nutrition on clinical outcomes and cost-effectiveness in gastric cancer populations after gastrectomy.
Methods
This retrospective cohort study included 150 gastric cancer patients after gastrectomy at Nanjing Drum Tower Hospital between September 2022 and September 2023. Patients were assigned to an omega-3 group and a control group based on whether they received postoperative omega-3 fish oil fat emulsion injection, with 53 matched pairs after propensity score matching (PSM). The primary outcome was the incidence of Grade II or higher complications. An economic evaluation was conducted from a hospital perspective, considering only direct medical costs over a 90-day horizon without discounting, using the incremental cost-effectiveness ratio (ICER). To evaluate the robustness of the primary findings, sensitivity analyses were performed using both one-way and probabilistic methods.
Results
After PSM, the omega-3 group demonstrated markedly lower incidences of both Grade II or higher complications (1/53 [1.9%] vs 9/53 [17.0%]; OR = 0.143, 95% CI: 0.015–0.656; P = 0.001) and intra-abdominal infection (0/53 [0%] vs 6/53 [11.3%]; OR = 0.073, 95% CI: 0.001–0.642; P = 0.014) than the control group. The white blood cell count on postoperative day 3 was significantly lower in the omega-3 group (P = 0.034). The cost-effectiveness analysis showed that the omega-3 group incurred an additional cost of 5,217.4 Chinese Yuan but achieved a 15.1% risk reduction in Grade II or higher complications, resulting in an ICER of 345.5. The probabilistic sensitivity analysis indicated a probability exceeding 98% that this strategy was more costly but more effective.
Conclusion
This retrospective single-center study observed an association between omega-3 fish oil emulsion and attenuated postoperative inflammation and complications. Although the intervention involved higher direct medical costs, these findings provide localized evidence for optimizing perioperative nutrition support.
Keywords: Omega-3 fatty acids, Gastrectomy, Complications, Cost-effectiveness analysis, Parenteral nutrition
Introduction
As one of the most prevalent and highly frequent malignant tumors, gastric cancer poses a considerable burden on global health, particularly in East Asian countries [1, 2]. China bore the heaviest burden worldwide in 2022, with about 509 thousand new cases and 400 thousand deaths [3]. The overall treatment strategy for gastric cancer is a comprehensive therapy centered on surgery, which is the primary treatment modality [4]. However, gastrectomy for gastric cancer is strongly associated with complication rates [5, 6], severely impacting patient survival and long-term prognosis, and imposing a heavy economic burden on society and families [7].
The active components of omega-3 fish oil fat emulsion injection are omega-3 polyunsaturated fatty acids (PUFAs), namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These PUFAs produce immunomodulatory and anti-inflammatory effects through multiple mechanisms. They competitively inhibit pro-inflammatory mediators derived from arachidonic acid and also promote the synthesis of pro-resolving mediators, like resolvins [8]. Furthermore, the emulsion is rich in α-tocopherol, which may help mitigate oxidative stress associated with inflammation [9]. Evidence indicates that perioperative supplementation with omega-3 fish oil emulsion can reduce postoperative infections, alleviate inflammatory responses, and lead to shorter length of stay (LOS) [10, 11]. The European Society for Clinical Nutrition and Metabolism (ESPEN) and Chinese guidelines also advocate for adding omega-3 fish oil emulsion to the postoperative parenteral nutrition (PN) regimen of cancer surgery populations [12, 13].
Standardized clinical nutritional therapy has promoted the wide application of omega-3 PUFAs. This expanded application has driven a rapid increase in demand, resulting in a corresponding rise in associated medical costs. Fish oil fat emulsion serves as a critical factor in clinical nutrition, influencing a spectrum of decisions from clinical choices to reimbursement policies, budget planning, and diagnosis-related group (DRG) standard setting. Therefore, it is of considerable practical importance to conduct a health economic evaluation of its cost-effectiveness and clinical benefits.
However, early research on omega-3 fish oil emulsion was primarily centered on clinical outcomes, while the economic impact received limited attention. Current economic studies on omega-3 fish oil emulsion are largely based on healthcare systems in Europe and the United States and mainly focus on critically ill or all inpatients [14–19]. There is a complete lack of cost-effectiveness analyses specifically targeting Chinese gastric cancer patients after gastrectomy. Under China's unique healthcare payment system and drug pricing structure, whether this intervention is cost-effective urgently requires validation from real-world research data. To address this research gap, a retrospective cohort study was conducted, representing the first cost-effectiveness analysis of omega-3 fish oil emulsion within a Chinese gastric cancer population. This study aimed to assess the clinical and economic impact of PN supplemented with omega-3 fish oil emulsion using a propensity score matching (PSM) method, providing real-world evidence for its perioperative application in Chinese gastric cancer patients.
Materials and methods
Study design
This retrospective cohort study enrolled gastric cancer patients who underwent gastrectomy at Nanjing Drum Tower Hospital from September 2022 to September 2023. The postoperative nutritional support followed a standardized and systematic protocol:
PN: All patients received standardized PN via central venous access from postoperative day (POD) 1 to POD 5. The base regimen was designed to provide 20–25 kcal/kg of energy, 1–1.5 g/kg/day of protein, and a total fat intake of 1–2 g/kg daily. Electrolytes (including sodium, potassium, chloride, calcium, phosphorous, and magnesium), multi-vitamins and trace elements were supplemented according to standard institutional guidelines and adjusted based on daily laboratory monitoring.
Enteral nutrition (EN): All patients transitioned to EN starting with glucose-sodium chloride or water (20–40 mL/h) on POD 1, followed by 500 kcal/day of EN from POD 2 to POD 5. PN was routinely discontinued on POD 6.
The primary difference between the two study groups was the lipid source utilized. Inclusion of an omega-3 fish oil emulsion injection was determined by the attending clinical team, based on an individualized assessment of surgical complexity, preoperative nutritional risk and comorbidities. The omega-3 group received daily PN supplemented with 1–2 mL/kg/day of omega-3 fish oil fat emulsion injection for at least 5 consecutive days starting from POD 1. The control group received standard PN without omega-3 supplementation.
All patients received standardized perioperative antibiotic prophylaxis as part of the routine postoperative care. A single dose was administered before incision, with intraoperative redosing if needed. Prophylaxis was discontinued within 48 h postoperatively unless signs of infection developed. Therapeutic antibiotics were only initiated upon clear clinical or laboratory evidence of infection, as assessed by the attending clinical team.
The intervention used in this study was the omega-3 fish oil fat emulsion injection (Fresenius Kabi Austria GmbH), which is approved for clinical use in China [National Medical Products Administration (NMPA) Approval Number: BH20050241]. The injection contains EPA and DHA at concentrations of 1.25–2.82 g and 1.44–3.09 g per 100 mL respectively, providing 112 kcal/100 mL.
Inclusion and exclusion criteria
Eligibility for the study required meeting all of the following conditions: (1) fulfilled the diagnostic criteria for gastric cancer and underwent gastrectomy; (2) received postoperative PN support for no less than 5 days; (3) age ≤ 80 years; (4) complete clinical medical records available.
Exclusion criteria included: (1) severe heart, brain, lung, liver, kidney dysfunction; (2) other metabolic diseases, including uncontrolled diabetes mellitus, dyslipidemia, or obesity; (3) active infection at the time of surgery or within 2 weeks preoperatively; (4) use of hormones, immunosuppressants, or immunomodulators within 6 months before surgery, or diagnosis of active autoimmune or immunodeficiency diseases; (5) unstable vital signs precluding the initiation of early postoperative PN.
Outcome measures
Baseline data were collected before surgery, representing preoperative levels. The primary outcome was the rate of Grade II or higher complications, including intestinal obstruction, intra-abdominal infection, delayed gastric emptying, and anastomotic leakage. Complications were diagnosed and recorded according to the list proposed by Baiocchi et al. [20], and infections were further defined based on the Centers for Disease Control and Prevention (CDC) criteria [21]. Grade II or higher complications were stratified using the Clavien-Dindo system [22]. Postoperative complications were assessed over a follow-up period of 90 days after surgery. The secondary outcomes comprised admission laboratory parameters [including white blood cell (WBC), neutrophil percentage (NEUT%), albumin (ALB), C-reactive protein (CRP), Interleukin-6 (IL-6)], and postoperative recovery outcomes (including time to first flatus, time to defecation, time to oral water intake, time to tolerance of liquid diet; postoperative LOS, total LOS).
Cost-effectiveness analysis
The cost-effectiveness analysis used a hospital perspective, guided by the China Guidelines for Pharmacoeconomic Evaluations (2020) [23]. The economic outcomes compared between the two cohorts included total hospitalization and medication costs. Total hospitalization costs were derived directly from expense bills prior to reimbursement. Indirect costs such as patient productivity loss and informal care costs were excluded. The 90-day costs of unplanned readmissions and reoperations associated with direct surgical complications were analyzed. Costs for routine outpatient follow-ups, emergency department visits without admission were excluded. Given the short-term horizon, no discounting was applied to costs or effects. Costs were expressed in Chinese Yuan (CNY). Measured effectiveness was assessed using the rates of Grade II or higher complications and intra-abdominal infection. The incremental cost-effectiveness ratio (ICER) was derived from the ratio of the intergroup cost difference to the effectiveness difference. No predefined willingness-to-pay threshold was used, given the absence of a validated Chinese threshold for clinical event rates.
Sensitivity analysis
An E-value analysis was performed to examine the robustness of the study outcomes and to assess the potential influence of unobserved confounders. A one-way sensitivity analysis was undertaken to assess the influence of single parameter uncertainty on the primary endpoints. This involved adjusting various parameters based on clinical data (including LOS, total hospitalization costs, complication rate, administration duration and cost of omega-3 fish oil emulsion). A probabilistic sensitivity analysis was conducted using a bias-corrected bootstrap procedure (10,000 replications) to account for parameter uncertainty and data skewness. The distribution of data points across the cost-effectiveness (CE) plane quadrants was examined to estimate the probability of cost-effectiveness for the intervention.
Statistical analysis
Quantitative data are expressed as mean ± standard deviation (SD) or median [interquartile range (IQR)], and categorical data as counts (%). Categorical data were analyzed using the χ2 test or Fisher's exact test as appropriate. Continuous data were analyzed using Student's unpaired t-test or Mann–Whitney U test. Statistical significance was set at a P-value of less than 0.05. First, baseline characteristics were compared between the omega-3 and control groups. Patients with omega-3 fish oil emulsion were matched 1:1 to those without omega-3 using nearest-neighbor matching with a caliper width of 0.02, without replacement. The use of a strict caliper aimed to maximize matching precision, consistent with the recommendation that lower caliper values reduce bias in matched estimates [24]. Propensity scores were derived via a logistic regression model incorporating the following baseline covariates: age, sex, tumor-node-metastasis (TNM) stage, body mass index (BMI), Nutrition Risk Screening 2002 (NRS 2002) score, history of hypertension and diabetes, history of previous surgery, receipt of chemotherapy, preoperative ALB and CRP level. All above were conducted using IBM SPSS Statistics (Version 27.0). Balance between the groups was considered adequate if the standardized mean difference (SMD) was below the threshold of 0.1 [25]. To further examine the independent association between omega-3 fish oil emulsion and the primary outcomes, a multivariable logistic regression analysis incorporating Firth’s penalization was performed. This analysis adjusted for residual confounding from baseline and intraoperative variables that exhibited an SMD > 0.1 after matching. Association strengths were reported as odds ratios (ORs) alongside their corresponding 95% confidence intervals (CIs). Records with missing data underwent manual source review for retrieval. Variables with > 20% missingness were excluded. For those below this threshold, multiple imputation by chained equations generated 10 complete datasets. Continuous variables were imputed via predictive mean matching and binary variables via logistic regression under multivariate normality. The final analytical dataset for PSM and outcome modeling was derived by pooling and averaging the results from multiple imputed datasets. These analyses were conducted via R (version 4.5.2).
Results
Patient characteristics
Figure 1 depicts the flowchart of the cohort selection. The study cohort, comprising 150 patients, was divided into an omega-3 group (n = 82) and a non-omega-3 group (n = 68). The two groups demonstrated comparable baseline characteristics across a range of demographic, clinical, and laboratory parameters, including gender, age, BMI, TNM stage, NRS 2002 score, surgical and chemotherapy history, as well as WBC, NEUT%, CRP, IL-6, ALB (all P > 0.05). With a markedly higher prevalence of diabetes in the omega-3 group (10/82 [12.2%] vs 2/68 [2.9%]; P < 0.05), the prevalence of hypertension did not differ significantly. After PSM, each group included 53 patients with no SMD exceeding 0.1 except for sex (Table 1).
Fig. 1.
The flow chart of present study
Table 1.
Baseline characteristics of patients before and after PSM
| Characteristics | Before PSM | After PSM | ||||||
|---|---|---|---|---|---|---|---|---|
| Omega-3 group | Control group | P value | SMD | Omega-3 group | Control group | P value | SMD | |
| (n = 82) | (n = 68) | (n = 53) | (n = 53) | |||||
| Sex, No. (%) | 0.733 | 0.056 | 0.504 | 0.130 | ||||
| Male | 57 (69.5) | 49 (72.1) | 41 (77.4) | 38 (71.7) | ||||
| Female | 25 (30.5) | 19 (27.9) | 12 (22.6) | 15 (28.3) | ||||
| Age, years (M, IQR) | 65.5 (56.0, 70.0) | 60.5 (56.3, 71.0) | 0.615 | 0.116 | 64.0 (56.0, 68.5) | 60.0 (55.0, 71.5) | 0.977 | 0.020 |
| TNM stage, No. (%) | 0.625 | 0.141 | 0.572 | 0.061 | ||||
| Tis | 2 (2.4) | 0 (0.0) | 2 (3.8) | 0 (0.0) | ||||
| I | 24 (29.3) | 16 (23.5) | 12 (22.6) | 12 (22.6) | ||||
| II | 21 (25.6) | 21 (30.9) | 16 (30.2) | 17 (32.1) | ||||
| III | 31 (37.8) | 28 (41.2) | 19 (35.8) | 22 (41.5) | ||||
| IV | 4 (4.9) | 3 (4.4) | 4 (7.5) | 2 (3.8) | ||||
| BMI, kg/m2 (M, IQR) | 23.0 (20.2, 25.3) | 23.6 (21.9, 25.6) | 0.197 | 0.177 | 23.5 (20.6, 25.6) | 23.3 (21.5, 25.3) | 0.924 | 0.055 |
| NRS 2002 score, No. (%) | 0.166 | 0.226 | 0.685 | 0.078 | ||||
| Score < 3 | 26 (31.7) | 29 (42.6) | 20 (37.7) | 18 (34.0) | ||||
| Score ≥ 3 | 56 (68.3) | 39 (57.4) | 33 (62.3) | 35 (66.0) | ||||
| Previous abdominal surgery, No. (%) | 14 (17.1) | 15 (22.1) | 0.441 | 0.125 | 8 (15.1) | 10 (18.9) | 0.605 | 0.100 |
| Comorbidity, No. (%) | ||||||||
| Hypertension | 19 (23.2) | 24 (35.3) | 0.102 | 0.267 | 14 (26.4) | 12 (22.6) | 0.652 | 0.088 |
| Diabetes | 10 (12.2) | 2 (2.9) | 0.038 | 0.353 | 3 (5.7) | 2 (3.8) | 0.647 | 0.089 |
| Chemotherapy, No. (%) | 15 (18.3) | 7 (10.3) | 0.168 | 0.229 | 5 (9.4) | 6 (11.3) | 0.750 | 0.062 |
| WBC, × 109/L (M, IQR) | 5.0 (3.8, 6.1) | 5.1 (4.1, 6.1) | 0.511 | 0.015 | 5.0 (3.9, 6.3) | 5.0 (4.1, 6.2) | 0.845 | 0.092 |
| NEUT, % (M, IQR) | 60.4 (53.9, 66.0) | 59.7 (53.9, 66.0) | 0.567 | 0.077 | 60.0 (53.4, 64.2) | 59.3 (52.8, 67.1) | 0.924 | 0.078 |
| CRP, mg/L (M, IQR) | 3.5 (3.0, 6.1) | 3.4 (2.7, 5.5) | 0.303 | 0.071 | 3.5 (3.1, 5.9) | 3.4 (2.7, 5.4) | 0.386 | 0.035 |
| IL-6, pg/mL (M, IQR) | 7.9 (6.0, 11.3) | 7.7 (4.0, 12.0) | 0.350 | 0.063 | 7.2 (4.8, 9.6) | 7.7 (3.8, 11.7) | 0.691 | 0.073 |
| ALB, g/L (mean, SD) | 37.4 ± 3.2 | 38.0 ± 2.5 | 0.105 | 0.241 | 37.7 ± 2.9 | 37.6 ± 2.5 | 0.104 | 0.028 |
Surgical history included appendicectomy, caesarean section/hysterectomy, cholecystectomy
M Median, IQR Interquartile range, TNM Tumor node metastasis, BMI Body mass index, NRS 2002 Nutrition risk screening 2002, WBC White blood cell, NEUT Neutrophil, CRP C-reactive protein, IL-6 Interleukin-6, Alb Albumin, SD Standard deviation, SMD Standardized mean difference
Some intraoperative variables, such as the type of gastrectomy and operative time, remained unbalanced between the two cohorts, as detailed in Table 2. The dataset demonstrated a high level of completeness, with less than 2% of data points missing.
Table 2.
Intraoperative characteristics of patients after PSM
| Characteristics | After PSM | |||
|---|---|---|---|---|
| Omega-3 group | Control group | P value | SMD | |
| (n = 53) | (n = 53) | |||
| Type of gastrectomy, No. (%) | 0.328 | 0.191 | ||
| Total gastrectomy | 27 (50.9) | 32 (60.4) | ||
| Subtotal gastrectomy | 26 (49.1) | 21 (39.6) | ||
| Extent of lymphadenectomy, No. (%) | 1.000 | 0.000 | ||
| D1 | 1 (1.9) | 1 (1.9) | ||
| D2 | 52 (98.1) | 52 (98.1) | ||
| Operative time, hour (M, IQR) | 3.0 (2.5, 3.5) | 3.0 (2.5, 3.4) | 0.754 | 0.153 |
| Bleed loss, mL (M, IQR) | 50 (50, 100) | 50 (50, 100) | 0.565 | 0.049 |
| Surgical team, No. (%) | 0.892 | 0.093 | ||
| Team A | 26 (49.1) | 28 (52.8) | ||
| Team B | 14 (26.4) | 12 (22.6) | ||
| Team C | 13 (24.5) | 13 (24.5) | ||
M Median, IQR Interquartile range
Primary outcomes
In postoperative complications, the intervention group had a significantly lower incidence of Grade II or higher complications (4/82 [4.9%] vs 10/68 [14.7%]; P = 0.049). The rate of intra-abdominal infection was markedly decreased in the omega-3 group (1/82 [1.2%] vs. 7/68 [10.3%]; P = 0.023). The analysis revealed no significant inter-group differences in other complications, including intestinal obstruction, delayed gastric emptying, and anastomotic leakage. Analysis after PSM illustrated that the intervention group still had significantly lower incidences of Grade II or higher complications (1/53 [1.9%] vs 9/53 [17.0%]; P = 0.016) and intra-abdominal infection (0/53 [0%] vs 6/53 [11.3%]; P = 0.027) (Table 3).
Table 3.
Grade II or higher complications before and after PSM
| Outcomes | Before PSM | After PSM | ||||||
|---|---|---|---|---|---|---|---|---|
| Omega-3 group | Control group | P value | Omega-3 group | Control group | P value | Multivariable | ||
| (n = 82) | (n = 68) | (n = 53) | (n = 53) | OR (95% CI) | P value | |||
| Grade II or higher complications, No. (%) | 4 (4.9) | 10 (14.7) | 0.049 | 1 (1.9) | 9 (17.0) | 0.016 | 0.143 (0.015, 0.656) | 0.001 |
| Bowel obstruction | 3 (3.7) | 1 (1.5) | 0.627 | 1 (1.9) | 1 (1.9) | 1.000 | 1.128 (0.089, 14.257) | 0.918 |
| Intra-abdominal infection | 1 (1.2) | 7 (10.3) | 0.023 | 0 (0.0) | 6(11.3) | 0.027 | 0.073 (0.001, 0.642) | 0.014 |
| Delayed gastric emptying | 0 (0.0) | 2 (2.9) | 0.204 | 0 (0.0) | 2 (3.8) | 0.495 | 0.161 (0.001, 2.166) | 0.183 |
| Anastomotic leakage | 0 (0.0) | 1 (1.5) | 0.453 | 0 (0.0) | 0 (0.0) | - | - | - |
CI Confidence interval, OR Odds ratio, - not applicable because no events occurred in either group after matching
Secondary outcomes
Compared to the non-omega-3 group, a significant decrease in WBC count on POD 3 was observed in the omega-3 group (6.8 × 10⁹/L [IQR 5.2–8.7] vs 8.5 × 10⁹/L [IQR 6.2–10.8]; P = 0.007). Following PSM, a significantly lower WBC count on POD 3 was still observed in the omega-3 group (7.1 × 10⁹/L [IQR 5.2–9.3] vs 8.2 × 10⁹/L [IQR 6.3–11.2]; P = 0.034). No statistically significant differences were observed in other laboratory parameters, including NEUT%, CRP, IL-6 and ALB (Table 4).
Table 4.
Postoperative laboratory parameters before and after PSM
| Parameters | Before PSM | After PSM | ||||
|---|---|---|---|---|---|---|
| Omega-3 group | Control group | P value | Omega-3 group | Control group | P value | |
| (n = 82) | (n = 68) | (n = 53) | (n = 53) | |||
| WBC, × 109/L | ||||||
| POD1 (mean, SD) | 11.5 ± 3.4 | 11.2 ± 3.0 | 0.130 | 12.1 ± 3.5 | 11.4 ± 3.1 | 0.265 |
| POD3 (M, IQR) | 6.8 (5.2, 8.7) | 8.5 (6.2, 10.8) | 0.007 | 7.1 (5.2, 9.3) | 8.2 (6.3, 11.2) | 0.034 |
| POD7 (M, IQR) | 6.7 (5.3, 8.5) | 6.8 (5.7, 8.3) | 0.789 | 6.7 (5.7, 8.3) | 7.1 (5.6, 8.4) | 0.882 |
| NEUT% | ||||||
| POD1 (M, IQR) | 88.4 (83.6, 90.5) | 86.7 (83.8, 89.6) | 0.320 | 88.4 (84.3, 90.3) | 86.4 (83.6, 89.6) | 0.245 |
| POD3 (M, IQR) | 77.9 (72.5, 84.1) | 80.7 (73.0, 84.0) | 0.597 | 76.6 (72.3, 84.1) | 80.5 (72.6, 84.0) | 0.371 |
| POD7 (M, IQR) | 71.0 (66.0, 75.9) | 70.6 (66.2, 75.0) | 0.514 | 70.1 (65.2, 76.1) | 69.6 (66.3, 74.8) | 0.688 |
| CRP, mg/L | ||||||
| POD1 (M, IQR) | 35.0 (20.0, 51.3) | 43.3 (23.1, 60.9) | 0.111 | 35.4 (17.6, 55.4) | 42.4 (21.5, 58.6) | 0.340 |
| POD3 (M, IQR) | 66.2 (45.4, 91.7) | 64.6 (47.7, 90.0) | 0.940 | 65.1 (41.8, 93.5) | 63.9 (48.1, 85.8) | 0.892 |
| POD7 (M, IQR) | 30.1 (14.9, 50.2) | 27.2 (17.6, 44.3) | 0.724 | 31.8 (15.3, 50.3) | 25.4 (15.4, 40.3) | 0.286 |
| IL-6, pg/mL | ||||||
| POD7 (M, IQR) | 18.0 (9.8, 24.1) | 17.1 (9.9, 23.2) | 0.621 | 16.8 (8.4, 23.1) | 18.0 (11.0, 24.7) | 0.515 |
| ALB, g/L | ||||||
| POD1 (mean, SD) | 35.1 ± 3.4 | 35.1 ± 3.0 | 0.180 | 35.5 ± 2.9 | 35.1 ± 3.1 | 0.910 |
| POD7 (mean, SD) | 35.1 ± 3.2 | 36.9 ± 2.8 | 0.360 | 35.5 ± 3.2 | 36.9 ± 3.0 | 0.641 |
WBC White blood cell, SD Standard deviation, M Median, IQR Interquartile range, POD Postoperative day, NEUT% Neutrophil percentage, CRP C-reactive protein, IL-6 Interleukin-6, ALB Albumin
The two groups were comparable in all recorded recovery and hospitalization outcomes before and after PSM (Table 5).
Table 5.
Postoperative recovery and hospital stay before and after PSM
| Outcomes | Before PSM | After PSM | ||||
|---|---|---|---|---|---|---|
| Omega-3 group | Control group | P value | Omega-3 group | Control group | P value | |
| (n = 82) | (n = 68) | (n = 53) | (n = 53) | |||
| Recovery time, day (M, IQR) | ||||||
| Time to first flatus | 4 (3, 4) | 4 (3, 4) | 0.967 | 4 (3, 4) | 4 (3, 4) | 0.835 |
| Time to first defecation | 5 (4, 6) | 5 (4, 6) | 0.974 | 5 (4, 6) | 5 (4, 6) | 0.932 |
| Time to first oral water intake | 6 (5, 6) | 6 (6, 7) | 0.055 | 6 (5, 6) | 5 (4, 6) | 0.158 |
| Time to tolerance of liquid diet | 7 (6, 7) | 7 (6, 7) | 0.361 | 7 (6, 7) | 7 (6, 7) | 0.938 |
| Length of stay, day (M, IQR) | ||||||
| Postoperative LOS | 10 (9, 11) | 10 (9, 12) | 0.561 | 10 (9, 11) | 10 (9, 12) | 0.859 |
| Total LOS | 15 (14, 18) | 15 (13, 18) | 0.494 | 15 (14, 18) | 14 (13, 17) | 0.147 |
M Median, IQR Interquartile range, LOS Length of stay
Adjusted regression analysis for covariate imbalance
After adjusting for baseline and intraoperative variables that showed an imbalance (SMD > 0.1) using multivariable logistic regression, omega-3 fish oil emulsion remained associated with a reduced risk of Grade II or higher complications (OR = 0.143, 95% CI: 0.015–0.656; P = 0.001) and intra-abdominal infection (OR = 0.073, 95% CI: 0.001–0.642; P = 0.014). No significant differences were found in the incidence of bowel obstruction and delayed gastric emptying (Table 3).
Cost-effectiveness analysis
A notable increase in total hospitalization costs was detected in the omega-3 group compared with the control group (78,267.3 ± 13,391.0 CNY vs 73,496.4 ± 13,811.8 CNY; P = 0.034). A further increase in medication costs was noted in the omega-3 group (19,309.5 ± 6,572.0 CNY vs 15,912.6 ± 6,579.8 CNY; P = 0.002). After PSM, total hospitalization costs were markedly higher in the omega-3 group (77,964.0 ± 13,488.3 CNY vs 72,746.7 ± 12,220.0 CNY; P = 0.039). Similarly, compared with the non-omega-3 group, the intervention group also incurred higher medication costs (19,074.4 ± 6,510.5 CNY vs 15,234.7 ± 4,637.6 CNY; P = 0.001) (Table 6).
Table 6.
Cost-effectiveness analysis before and after PSM
| Costs | Before PSM | After PSM | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Omega-3 group | Control group | Omega-3 group | Control group | |||||||||
| (n = 82) | (n = 68) | P value | (n = 53) | (n = 53) | P value | |||||||
|
Total hospitalization costs CNY (mean, SD) |
78,267.3 ± 13,391.0 | 73,496.4 ± 13,811.8 | 0.034 | 77,964.0 ± 13,488.3 | 72,746.7 ± 12,220.0 | 0.039 | ||||||
|
Medication cost CNY (mean, SD) |
19,309.5 ± 6572.0 | 15,912.6 ± 6579.8 | 0.002 | 19,074.4 ± 6510.5 | 15,234.7 ± 4637.6 | 0.001 | ||||||
| Outcomes | ΔE (%) | ΔC (CNY) | ICER | CE plane (%) | ΔE (%) | ΔC (CNY) | ICER | CE plane (%) | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| NE | NW | SE | NE | NW | SE | |||||||
| Grade II or higher complication |
9.8 (0.2, 19.5) |
4770.9 (353.9, 9188.0) |
486.8 | 96.5 | 1.8 | 1.7 |
15.1 (4.3, 25.8) |
5217.4 (259.1, 10,175.6) |
345.5 | 98.1 | 0.1 | 1.8 |
| Intra-abdominal infection |
9.1 (1.5, 16.7) |
4770.9 (353.9, 9188.0) |
524.3 | 97.7 | 0.6 | 1.7 |
11.3 (2.8, 19.9) |
5217.4 (259.1, 10,175.6) |
461.7 | 98.2 | 0 | 1.8 |
M Median, SD Standard deviation, ICER Incremental cost-effectiveness ratio, △C Cost difference, △E Effectiveness difference, CE plane Cost-effectiveness plane quadrant, NE (northeast) intervention is more costly and more effective, NW (northwest) more costly and less effective, SE (southeast) less costly and more effective
The ICER analysis revealed that total hospitalization costs were increased by 4,770.9 CNY (95% CI: 353.9–9,188.0) (ΔC) in the omega-3 group, while the Grade II or higher complications rate was significantly decreased by 9.8% (95% CI: 0.2–19.5) (ΔE). The calculated ICER was 486.8 CNY per 1% absolute drop in the rate of Grade II or higher complications. It was indicated that every 1% decrease in the Grade II or higher complication rate required an additional investment of 486.8 CNY in hospitalization costs. The intra-abdominal infection rate showed a significant decrease of 9.1% (95% CI: 1.5–16.7). The calculated ICER was 524.3 CNY per 1% absolute reduction in intra-abdominal infection incidence. After PSM, the total hospitalization cost in the omega-3 group increased by 5,217.4 CNY (95% CI: 259.1–10,175.6), and the incidence of Grade II or higher complications decreased significantly by 15.1% (95% CI: 4.3–25.8). The calculated cost per 1% absolute gain in the avoidance of Grade II or higher complications amounted to 345.5 CNY. An 11.3% (95% CI: 2.8–19.9) relative risk reduction for intra-abdominal infection was observed in the omega-3 group. The calculated cost per 1% absolute reduction in intra-abdominal infection incidence was 461.7 CNY (Table 6).
Sensitivity analyses
The minimal strength that an unmeasured confounder would need to have to bias the results was estimated. The E-value for Grade II or higher complications was 13.47, and for intra-abdominal infection was 26.89. The substantial E-value obtained in this analysis reinforces the reliability of the results. This indicates that to negate the identified association between omega-3 fish oil emulsion and reduced complication rates, any unmeasured confounding factors would require an exceptionally strong effect size.
The results of the one-way sensitivity analysis are displayed in Fig. 2. The ICER was most sensitive to variations in total hospitalization costs and LOS. In contrast, parameters including cost and administration duration of omega-3 fish oil emulsion, and complication rate of each group, exerted a comparatively minor influence on the model outcomes. Moreover, some ICER values were below zero. It indicates that under certain scenarios, the omega-3 intervention could simultaneously reduce costs and lower complication rates, representing a cost-saving and clinically advantageous strategy.
Fig. 2.
The tornado diagram of the one-way sensitivity analysis. Parameter ranges were defined as follows: hospitalization costs, LOS, intra-abdominal infection rate, and grade II or higher complication rate were based on median and interquartile ranges from the retrospective study; administration duration was varied by ± 30% of the base-case value; and the unit cost of omega‑3 fish oil fat emulsion was varied by ± 20% of the base-case value. ICER, incremental cost-effectiveness ratio; LOS, length of stay
In probabilistic sensitivity analysis, for Grade II or higher complications, the CE plane based on total hospitalization costs demonstrated that 96.5% of bootstrap replications fell in the first quadrant, 1.8% in the second quadrant, and 1.7% in the fourth quadrant before matching (Fig. 3A). After PSM, the distribution shifted to 98.1% in the first quadrant, 0.1% in the second quadrant, and 1.8% in the fourth quadrant (Fig. 3B). For intra-abdominal infection, the pre-matching analysis revealed 97.7% of points in the first quadrant, 0.6% in the second quadrant, and 1.7% in the fourth quadrant (Fig. 3C). After PSM, 98.2% of replications were located in the first quadrant, with 1.8% in the fourth quadrant (Fig. 3D).
Fig. 3.
Incremental cost-effectiveness scatter plots. A and C present pre-PSM analyses (n = 150), while B and D present post-PSM analyses (n = 106). Horizontal axes show between-group differences in incidence rates of grade ≥ II complications (A, B) and intra-abdominal infections (C, D); vertical axes display incremental total direct healthcare costs
Discussion
This PSM analysis suggests a potential benefit of omega-3 fish oil emulsion in postoperative PN for improving clinical outcomes. The lower WBC counts observed on POD 3 in the omega-3 group offer preliminary insights into the possible anti-inflammatory effects of omega-3 PUFAs. The effect is likely mediated through the competitive inhibition of arachidonic acid metabolism by omega-3 PUFAs, a mechanism that reduces pro-inflammatory mediators [8, 9]. This modulated inflammatory response may foster a microenvironment more conducive to tissue repair and infection control [26]. It might be the potential intrinsic physiological basis for the lower incidences of Grade II or higher complications and intra-abdominal infection in the intervention group. Two large-scale meta-analyses [10, 27] consistently confirmed that supplementing PN with omega-3 fish oil emulsion, compared to traditional lipid emulsions, has a significant advantage in reducing postoperative infection rates. These previous studies are consistent with the present findings. However, the clinical implications in this research should be interpreted cautiously. While statistically significant, the overall effect was modest. The complete absence of intra-abdominal infections in one group, in particular, is a noteworthy finding, though it may be limited by the sample size. This suggests that the intervention should be considered in light of individual patient risk profiles and resource availability.
Inconsistent conclusions as to the impact of omega-3 fish oil emulsion on nutritional indicators in patients after gastrectomy have been found in the literature. Several studies showed it could significantly increase ALB levels [28, 29], while others reported no statistically significant inter‑group difference [30, 31]. No significant nutritional advantage was observed for omega-3 fish oil emulsion in enhancing postoperative ALB levels. A reasonable explanation for this result may include: postoperative acute-phase serum protein levels are more influenced by factors such as inflammation, stress, and fluid balance, and the effect of short-term nutritional intervention might be masked [32]; second, although a standardized postoperative nutrition support protocol was followed, this remains an observational study. In real-world practice, inter-individual variations in EN tolerance and the speed of achieving target feeding volumes may still exist. These factors could confound the accurate attribution of short-term changes in nutritional parameters such as ALB. This suggests that the core benefit of omega-3 fish oil emulsion might first manifest in its anti-inflammatory and immunomodulatory functions rather than direct nutritional support.
Furthermore, perioperative inflammation is a key driver of systemic organ injury, which affects millions of surgical patients and substantially increases mortality risk [33, 34]. The findings suggest that omega-3 fish oil emulsion was associated with attenuated postoperative inflammatory response. Given that this inflammatory milieu is implicated in both overt organ dysfunction and subtler subclinical alterations [35], the results provide preliminary evidence that warrants further investigation: omega-3 fish oil emulsion may mitigate not only local complications, such as surgical site infections, but also the spectrum of surgery-induced, inflammation-mediated organ stress. Future trials with comprehensive multi-organ monitoring are warranted to test this promising possibility.
In terms of health economics, this research provides the first preliminary and context-specific cost-effectiveness evidence for omega-3 fish oil emulsion in Chinese gastric cancer surgery populations. The analysis indicates that an incremental cost of approximately 345.5 CNY is required to achieve a 1% absolute risk reduction in Grade II or higher complications. Importantly, interpreting whether this incremental cost represents definitive cost-effectiveness is constrained by the absence of an established willingness-to-pay threshold for the avoidance of specific complications. However, these cost data were highly variable, with wide 95% CIs around the incremental cost and effectiveness estimates. This heterogeneity suggests that the economic impact of this intervention is not uniform and may vary across different patient subgroups or clinical pathways. Although the probabilistic sensitivity analysis indicated a high probability (> 98%) that the strategy is more effective at an increased cost, this conclusion remains specific to the studied context and warrants validation in broader, prospective studies before generalized policy or clinical recommendations can be made.
The “effective but more expensive” profile contrasts with the cost-saving effects of omega-3 fish oil emulsion reported in European and American hospitalized populations [14–19]. Early economic research on PN containing omega-3 PUFAs was primarily centered on critically ill patients [14–17], and later extended to broader hospitalized populations. For instance, a 2020 European study involving all hospitalized patients confirmed that PN containing omega-3 PUFAs had better clinical efficacy and significantly lower average treatment costs, saving €1,741–€5,576 per adult hospitalized patient [18]. Another systematic review and cost-effectiveness analysis focusing on non-intensive care unit (non-ICU) inpatients further showed that PN containing fish oil was correlated with a lower risk of infectious complications and favorable economic value across diverse healthcare settings [19]. But it is not appropriate to directly extrapolate these findings to Chinese post-gastrectomy patients.
The results demonstrate a discrepancy that is speculated to stem from several factors, highlighting the limited external validity of the economic findings beyond the specific healthcare system studied. Firstly, the healthcare systems, drug pricing, and cost structures involved in European studies are significantly different from those in China. The high hospitalization costs saved by reducing complications in their studies were sufficient to cover the incremental cost of omega-3 fish oil emulsion; whereas under China's current payment system, daily medical costs are relatively lower, with consequently limited economic savings from the same clinical benefit. Secondly, the subjects of this study were elective gastric cancer surgery patients, whose risk of complications might be relatively lower compared to the more heterogeneous critically ill patients [36], thus resulting in relatively lower medical expenses. Thirdly, the specific imported omega-3 fish oil emulsion preparation used in this study is expensive, constituting a significant incremental cost compared to standard Chinese PN regimens. Fourthly, from the standpoint of the healthcare service system, the economic analysis concentrated primarily on direct medical costs. If a broader societal perspective were adopted, including indirect costs such as patient lost productivity due to complications and family care costs, the economic profile of this intervention might appear more favorable. Furthermore, when interpreting this result, a prospective economic perspective is needed. Given the substantial costs associated with severe complications (e.g., secondary interventions and extended stays), this upfront investment might offer long-term cost-saving potential for this patient cohort. Future research should combine longer-term prognosis data and more comprehensive cost accounting to further verify its long-term economic value.
Strengths and limitations
The primary strengths of this study are characterized by several key aspects. First, this study focus on Chinese gastric cancer patients after gastrectomy, providing the first context-specific cost-effectiveness evidence for omega-3 fish oil emulsion in this population. Secondly, a comprehensive statistical framework, integrating PSM, multivariable logistic regression, and E-value analysis, was implemented to rigorously control for selection bias and residual confounding, thereby ensuring the validity of the clinical outcomes. Thirdly, the economic evaluation was validated through one-way and probabilistic sensitivity analyses, which effectively addressed parameter uncertainty and confirmed the robustness of the cost-effectiveness model across various clinical scenarios. Moreover, the high data integrity, with a missing rate below 2%, ensures the reliability of this real-world evidence for clinical and economic decision-making.
This study is subject to several limitations. Firstly, the retrospective design and non‑randomized allocation of omega‑3 supplementation may introduce selection bias. Although PSM was employed to balance baseline covariates and further adjustment was performed for residual intraoperative confounders, unmeasured factors could still influence the results. Additionally, due to the limited events-per-variable ratio, the multivariable regression analyses may be susceptible to model overfitting; thus, these findings should be interpreted as exploratory. Secondly, the control group received various standard lipid emulsions per routine practice, rather than a single and matched control emulsion. This real-world design enhances external validity but implies differences between groups are not isolated to the presence or absence of omega-3 fish oil emulsion. Variability in other emulsion components could theoretically confound the observed outcomes. Thirdly, the single‑center design limits the external validity of the findings. Direct extrapolation to other centers or regions should be cautious, given potential variations in patient populations, clinical protocols, and healthcare economics. In addition, the statistical power for specific secondary outcomes, like CRP and LOS, may be limited by the sample size. Further validation of these findings through larger-scale multi-center cohort studies or randomized controlled trials (RCTs) is warranted. Another significant limitation is the inability to comprehensively control for several key perioperative factors. Although perioperative care followed standardized protocols, unmeasured variations in adherence and residual confounding related to patient physiology remain inherent limitations of this retrospective analysis. Moreover, the monitoring time points of postoperative inflammation and nutritional indicators in this study were limited and restricted the in-depth analysis of the complete dynamic trajectories of these indicators. Regarding the economic evaluation, although probabilistic and one-way sensitivity analyses were conducted, these were based on the parameter uncertainty within the single-center dataset. More complex scenario analyses or threshold analyses based on external willingness-to-pay benchmarks were not performed. Last but not least, the cost-effectiveness analysis was conducted from a short-term hospital perspective. This research does not capture potential long-term economic impacts or indirect costs beyond the initial hospitalization period.
Future research should be based on multi-center RCTs and standardized treatment regimens with comprehensive data collection on perioperative factors. By combining more frequent and continuous postoperative monitoring time points, researchers can precisely map the dynamic progression of inflammatory and nutritional biomarkers. Cost-effectiveness analyses should adopt a broader perspective that includes long-term outcomes and indirect costs. This method not only helps to clarify the intrinsic mechanisms and clinical benefits of omega-3 fish oil emulsion but also provides robust evidence for its implementation and economic value.
Conclusion
In this retrospective single-center study, omega-3 fish oil emulsion was associated with reduced postoperative WBC levels and inhibition of excessive inflammatory responses. It appeared to be beneficial for promoting early patient recovery and reducing postoperative complications, particularly intra-abdominal infections. It represents a more effective but more costly therapeutic intervention strategy. This cost-effectiveness analysis provides Chinese economic evidence for perioperative nutritional support practice. These findings provide an evidence-based foundation for clinicians to integrate omega-3 fish oil into postoperative nutrition protocols, especially for patients at high risk of infection, to enhance surgical safety and care quality. Although more expensive, this upfront investment may mitigate the severe clinical burden of postoperative complications. This also holds significant implications for future clinical practice and research.
Acknowledgements
The authors are sincerely thankful to the Department of General Surgery and the Department of Pharmacy of Nanjing Drum Tower Hospital.
Authors’ contributions
X.L., L.L., and X.B. contributed to the conception and design. Y.Y., X.W., M.Z., H.W., L.T. and H.Z. contributed to analysis and interpretation of data. X.L. drafted the manuscript. All authors reviewed the manuscript. All authors contributed to data acquisition.
Funding
The study had no funding support.
Data availability
This published article contains all data analyzed in this study.
Declarations
Ethics approval and consent to participate
Following approval from the Medical Ethics Committee of Nanjing Drum Tower Hospital, Affiliated to Nanjing University Medical School (AF/SC-08/03.0), this retrospective study was conducted in conformity with the Declaration of Helsinki, and informed consent was dispensed with.
Consent for publication
Consent for the publication of the article was obtained from all authors.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Xuan Luo and Yu-Xing You contributed to the work equally and should be regarded as Co-first authors. Li Li and Xiao-Jie Bian contributed to the work equally and should be regarded as co-corresponding authors.
Contributor Information
Li Li, Email: njgllily@163.com.
Xiao-Jie Bian, Email: 18061678828@189.cn.
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Data Availability Statement
This published article contains all data analyzed in this study.