#IDIBELLfellows: Ana Suárez-Lledó Grande

Effect of parenteral supplementation with fish oil on the standard nutritional support of esophagectomized patients
Ana Suárez-Lledó Grande – Pharmacotherapy, pharmacogenetics and pharmaceutical technology

Introduction: Parenteral nutrition (PN)-associated hepatopathy (PAH) is one of the main complications resulting from the infusion of lipid emulsions (LE) in PN, and has been associated with the presence of phytosterols. In fact, throughout the evolution of PN components, a strategy has been adopted to reduce caloric intake by restricting lipid use. The choice of LE is clinically relevant due to its metabolic and immunomodulatory effects. The use of fish oil (FO)-based LE, due to its immunomodulatory effect, its being free of phytosterols, and its better control of hypertriglyceridemia, makes them especially useful in patients with high nutritional requirements and/or inflammatory response associated with metabolic stress. Larger surgeries such as esophagectomy involve high catabolism and a postoperative inflammatory response, which is associated with high morbidity and mortality. Omega-3 (ω3) fatty acids (FAs) administered enterally, despite low tolerance, have shown anti-inflammatory and immunomodulatory efficacy. There are few clinical trials using ω3 FAs administered intravenously, and in all of them, their administration is as part of PN. There is no clinical experience with the administration of LE parenterally as a complement to standard enteral nutrition (EN). This thesis presents the first study administering ω3 FAs intravenously as the sole pharmaconutrient, without being formulated as PN associated with carbohydrates or proteins, at higher doses and combined alongside standard EN.

Hypothesis: Liver damage caused by PN administration is due not only to the presence of phytosterols, but also to the presence of an inflammatory response that can act synergistically, maximizing PAH between both factors. The use of FO-based LE may be beneficial in controlling the early inflammatory response, hepatic function alterations associated with PN, and in reducing hypertriglyceridemia, when compared to long-chain triglyceride (LCT) and medium-chain triglyceride (MCT) combination LE. The intravenous administration of ω3 FAs allows for the rapid incorporation of lipids into cell membranes and the inflammatory cascade. The use of FO intravenously, as a complement to EN, could be associated with better nutritional and clinical progression of the patient, reducing morbidity and mortality.

Objectives: First, to determine if liver damage, measured as alterations in liver function tests (LFTs), associated with PN administration is solely due to the presence of phytosterols, or if there is a synergistic effect related to a post-stress hepatic inflammatory response contributing to PAH. Second, to determine if the intravenous administration of FO-based LE in esophagectomized patients is effective in normalizing interleukin 6 (IL-6) compared to LCT/MCT FA, and whether doses of 0.8 g/kg/day are more effective than 0.4 g/kg/day. Secondary objectives: to evaluate the behavior of other inflammation markers (C-reactive protein -CRP-, tumor necrosis factor alpha -TNFα-, IL-10, IL-8, and soluble CD25 receptor -CD25-), triglyceridemia, morbidity, safety, nutritional follow-up, and mortality.

Methods: Two studies were conducted. The first was designed as a prospective observational study on a previously studied population that had received PN for at least 7 days and had shown liver dysfunction. A second prospective, single-center, randomized, double-blind study was conducted in esophagectomized patients. The standard EN support was supplemented with FO-based LE in continuous infusion for 5 days following surgical intervention (SI). The included patients were randomized 1:1:1 into three groups: Group A: 0.4 g/kg/day of FO and 0.4 g/kg/day of LCT/MCT emulsion; Group B: 0.8 g/kg/day of FO-based LE; Group C: 0.8 g/kg/day of LCT/MCT emulsion. Samples were collected at the time of SI and on days 0, 1, 3, 5, and 21 post-SI. Clinical follow-up was conducted for up to 1 year post-SI.

Main results: In the first study, the multivariate approach significantly associated various fractions of phytosterols and interaction variables between phytosterols and interleukins with GGT and ALT values. Post-stress inflammation in the presence of plasmatic phytosterols has a synergistic effect in worsening liver function. In the second study, the administration of ω3 FA-based LE did not modulate the early postoperative inflammatory response. Significant differences were found in the temporal evolution of IL-6 and CRP, but not when studying the type of emulsion administered or the need for intensive care. The administration of ω3 FA was found to be safe and significantly reduced plasma triglyceride levels in a dose-dependent manner.

 Conclusions: Liver damage resulting from PN administration is due not only to the presence of phytosterols, but also to a synergistic effect from the inflammatory response. Intravenous administration of ω3 FAs as a complement to standard EN has no impact on the early postoperative inflammatory response when evaluated over a short period. However, its safety at the studied doses and the rapid reduction in plasma triglyceride levels make it especially useful in patients with PAH or at risk of developing it, as well as in patients with hypertriglyceridemia. These results pave the way for studies with larger cohorts, particularly in major surgery patients who present a more sustained postoperative inflammatory response due to postoperative complications (septic or metabolic) or comorbidities.