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Background  Prospective randomized controlled trials (PRCTs) that found harm in patients receiving higher levels of energy exposure have been largely ignored, in part because of the lack of a known mechanism of harm.    Objective  The current 7‐day pilot study is a PRCT and post hoc analysis designed to explore the relationship between energy exposure and oxidative stress (as plasma total F2‐isoprostanes) in mechanically ventilated intensive care unit patients with systemic inflammatory response syndrome.    Methods  Thirty‐five participants were randomized to receive either 100% or 40% of their estimated energy needs. Our intent‐to‐treat model found no differences in F2‐isoprostanes between groups. A post hoc analysis revealed that on days when participants were in the highest tertile of daily kcal/kg, the real‐time energy flow rate within 2 hours of the blood draw was predictive of increased oxidative stress. On these days, participants in the second or third vs the first tertile of real‐time energy flow rate experienced a 41.8% ( P  = .006) or 26.5% ( P  = .001) increase in F2‐isoprostane levels, respectively. This was confirmed through a within‐group subanalysis restricted to participants with measurements on both sides of the median of real‐time energy flow rate that found a 28.2% F2‐isoprostane increase on days in the upper vs lower median of flow rate ( P  = .002).    Conclusion  The benefits of feeding may be more nuanced than previously suspected. Our findings imply a potential mechanism of harm in meeting the current recommendations for nutrition support in the critically ill that warrants further investigation.

Real‐Time Energy Exposure Is Associated With Increased Oxidative Stress Among Feeding‐Tolerant Critically Ill Patients: Results From the FEDOX Trial