The impact on ICU patients of new enteral nutrition formula designed to maintain autophagy that is low in carbohydrates and leucine and high in lipids

<h2>Summary</h2><h3>Background & aims</h3> Given that the ESPEN 2019 guidelines state that "severe hypophosphatemia may lead to death after the initiation of feeding in patients admitted to intensive care unit (ICU)," we have been developing enteral nutrition (EN) formulas designed to reduce the risk of hypophosphatemia. Preliminary research indicates that high glucose concentrations and leucine-rich peptides are associated with hypophosphatemia across EN formulas with varying nutrient compositions. Additionally, recent randomized controlled trials have shown that high macronutrient doses, irrespective of the delivery route, may be harmful during the acute phase of critical illness, possibly due to the suppression of autophagy and ketogenesis, overfeeding-related hyperglycemia, and increased insulin requirements. EN formulas with lower glucose and leucine contents and higher lipid concentrations may activate autophagy and ketogenesis by inhibiting the mammalian target of rapamycin (mTOR) pathway. This study aimed to evaluate the clinical effect of a newly developed EN formula in critically ill patients. <h3>Methods</h3> A newly developed EN formula was launched in September 2023. The composition of the new EN product is characterised by being low in carbohydrates, high in protein from peptides with low leucine content, and high in lipids. This single-center, retrospective cohort study was conducted in Japan to compare clinical outcomes between the new EN formula and the standard formula. Eligible patients were those admitted to the ICU for at least 10 days and requiring invasive mechanical ventilation for at least 3 days. Patients were categorized into the new EN group or standard EN group based on the enteral formula they received. The primary outcome was in-hospital mortality. Secondary outcomes included insulin doses and electrolyte levels (potassium, phosphate, and magnesium), bowel movement frequency, and the incidence of bowel ischemia. The baseline characteristics were adjusted using propensity score matching (PSM) and inverse probability of treatment weighting (IPTW), followed by multivariate logistic regression analysis. <h3>Results</h3> Among the 689 eligible patients, 262 were assigned to the new EN group and 427 to the standard EN group. After PSM, 230 patients were included in each group. In IPTW analysis, 682 patients with complete data were included in the weighted population. The doses of insulin and electrolytes (potassium, phosphate, and magnesium) were consistently lower in the new EN group in both PSM and IPTW analyses. The in-hospital mortality was significantly lower in the new EN group than in the standard EN group (25 [10.9%] vs. 48 [20.9%], <i>P</i> = 0.006 after PSM; <i>P</i> = 0.002 after IPTW). Logistic regression analysis demonstrated that the new EN formulation was significantly associated with reduced in-hospital mortality both after PSM (OR: 0.46, 95% CI: 0.25–0.80, <i>P</i> = 0.007) and IPTW adjustment (OR: 0.44, 95% CI: 0.26–0.74, <i>P</i> = 0.002). Additionally, higher parenteral calorie intake was significantly associated with increased mortality in both models (PSM: OR: 1.10, 95% CI: 1.02–1.19, <i>P</i> = 0.013; IPTW: OR: 1.08, 95% CI: 1.01–1.15, <i>P</i> = 0.020). <h3>Conclusion</h3> This study demonstrated that the new EN formulation was associated with significantly lower in-hospital mortality in critically ill ventilated patients, highlighting its potential to improve outcomes through optimized nutritional support.