Medical cost analysis

Only one trial reported nutrition therapy cost and total cost,16 and there was no significant difference between the groups in total cost (CN¥38,025±389.6 vs 37,968±563.5, P>0.05), although the omega-3 group had significantly higher nutrition therapy cost (4,025±309.6 vs 2,568±445.2, P<0.01).


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Sensitivity analysis

Through changing the synthesis model, sensitivity-analysis results demonstrated that the trends of pre- or postoperative infectious complications, TNFα, and hospital stay did not alter, while the trends of overall infectious complications (RR 0.6, 95% CI 0.34–1.06; P=0.51) and IL-6 (SMD −0.4, 95% CI −0.82 to 0.02; P=0.06) changed.

Publication bias

Publication bias may have existed in postoperative total complications and hospital stay, while there were low risks of publication bias in outcomes of postoperative infectious complications and SSI.

DISCUSSION

CRC surgery is associated with a high incidence of postoperative infections. The infections always led to prolonged hospital stay, increased medical cost, and even treatment failure. Underlying mechanisms included preoperative intestinal cleansing unsatisfied with residual feces in the colon, intraoperative incision of the colon and postoperative anastomotic leakage, which would highly increase the risk of bacterial contamination to the peritoneal cavity and surgical wound, together with the suppressed host immune function due to cancer and surgery stress. Among them, impaired immune status in CRC patients and acute stress of CRC surgery were considered to be the most important factors.12 In animal and observational clinical studies, omega-3 PUFA-enriched immuonutrition was reported to have antiplatelet, anti-inflammatory, antiangiogenic, and anti-CRC functions.7,23,24

To the best of our knowledge, the current study is the first meta-analysis focused on the clinical efficacy of short-term omega-3 PUFA immuonutrition in the prevention of specific CRC patients at very high risk of infection. Our study demonstrated significant benefits for infectious complication prevention, as well as serum inflammatory cytokines and hospital stay improvements, while no significant influence was found for total complications, SSI, or total medical cost.

Meta-analysis results in a fixed-effect model showed that the omega-3 group had a lower rate of postoperative infectious complications compared with the control group (15.6% vs 24.8%), and the reported infectious complications included the respiratory tract, urinary tract, abdominal abscess, bacteremia, and wound infection. Further subgroup analyses according to timing of omega-3 PUFA administration revealed that this significant difference would have been mainly contributed to by the pre- or postoperative subgroup. Perioperative omega-3 PUFA-enriched nutrition was administered for 9–14 days, while pre- or postoperative omega-3 PUFAs were always administered for 5–7 days. As such, the perioperative subgroup had an obviously longer duration of administration than pre- and postoperative subgroup, while no significant difference was found in the perioperative group. With regard to the optimal timing of immuonutrition administration, some studies stated preoperative nutrition may be helpful for the body to obtain an adequate level in time for the stress of surgery, and early postoperative nutrition was important issue fast recovery of intestinal function and psychological status.13,25 A recent network meta-analysis indicated that perioperative enteral immuonutrition (EIN) was better than pre- and postoperative EIN for postoperative infectious complication prevention.26 The network analysis also revealed that the timing of nutrition support seemed to have different influences on different outcome measures.

Possible explanations of the negative result of perioperative omega-3 PUFA administration in the current study were as follows. First, the sample size in the perioperative subgroup may be under the test power. It has been reported that 148 cases were enough to detect a 20% reduction in the rate of infectious complications,19 whereas an expected reduction in our study was only 9.2%, and thus nearly 300 cases were required (when β=0.8, α=0.05). Second, the perioperative subgroup included only patients receiving EIN orally or through an enteral tube, while the postoperative group included patients receiving PN through intravenous infusion. For postoperative nutrition administration, EN had advantages in aspects of commensal bacteria balance and intestinal function recovery, and was also a key intervention in the principle of fast-track surgery.13,27 Gastric paralysis lasted for 24 hours, colon dysfunction lasted for about 48 hours after abdominal surgery,13,28 and the time would be even longer in elective CRC surgery. Therefore, omega-3 PUFA-enriched EIN in the perioperative group during the early postoperative period may have been badly absorbed and utilized. Third, the different dose and formulation of omega-3 PUFAs in the studies might also have had an influence to the outcomes.

The current study also investigated changes in inflammatory cytokines, and the results showed that serum levels of TNFα and IL-6 were lower, demonstrating the anti-inflammatory role of omega-3 PUFAs. Both of the two cytokines would induce CD4+ T cells differentiated from different T-helper (Th) cells, and the levels of TNFα/IL-6 to some extent reflected the situation of Th1–Th2 cell balance. Th1 cells mainly mediate cellular immune response and play important roles in infection and tumor defense, while Th2 cells mainly mediate humoral immune response. CRC patients always had a Th1–Th2 imbalance shifted to Th2, and together with surgery stress this imbalance was enhanced and reported to be highly associated with postoperative infections.29,30 However, sensitivity analysis in our study suggested that IL-6 changes were not stable, so whether omega-3 PUFA-enriched nutrition modulated the Th1–Th2 balance or not was unclear. Due to the limited studies, its effects on CD4+ and CD8+ T-cell balance was also unclear.