This comprehensive narrative review summarizes relevant antioxidant mechanisms, the antioxidant status, and effects of supplementation in critically ill patients for the most studied antioxidant vitamins A, C, and E and the enzyme cofactor trace elements selenium and zinc. Over the past 15 years, oxidative stress-mediated cell damage has been recognized to be fundamental to the pathophysiology of various critical illnesses such as acute respiratory distress syndrome, ischemia-reperfusion injury, and multiorgan dysfunction in sepsis. Related to these conditions, low plasma levels of antioxidant enzymes, vitamins, and trace elements have been frequently reported, and thus supplementation seems logical. However, low antioxidant plasma levels per se may not indicate low total body stores as critical illness may induce redistribution of antioxidants. Furthermore, low antioxidant levels may even be beneficial as pro-oxidants are essential in bacterial killing. The reviewed studies in critically ill patients show conflicting results. This may be due to different patient populations, study designs, timing, dosing regimens, and duration of the intervention and outcome measures evaluated. Therefore, at present, it remains unclear whether supplementation of antioxidant micronutrients has any clinical benefit in critically ill patients as some studies show clear benefits, whereas others demonstrate neutral outcomes and even harm. Combination therapy of antioxidants seems logical as they work in synergy and function as elements of the human antioxidant network. Further research should focus on defining the normal antioxidant status for critically ill patients and to study optimal supplement combinations either by nutrition enrichment or by enteral or parenteral pharmacological interventions.

Our data suggest that although overall low protein intake is associated with the highest mortality risk, high protein intake during the first 3-5 days of ICU stay is also associated with increased long-term mortality. Therefore, timing of high protein intake may be relevant for optimizing ICU, in-hospital and long-term mortality outcomes.

Refeeding syndrome is common among prolonged mechanically ventilated critically ill patients, however not predictable by baseline characteristics. Among patients that develop refeeding syndrome low caloric intake was associated with a reduction in 6-month mortality risk. This effect was not seen in patients without refeeding syndrome. Findings support caloric restriction in refeeding syndrome during critical illness.

YCLNU-D-17-01092R2.

Background The optimal nutritional support for critically ill septic patients remains unknown. This study evaluates the associations of macronutrient intake during the first week of intensive care unit (ICU) admission and long‐term clinical outcomes in septic and non‐septic patients. Methods Prolonged mechanically ventilated patients were retrospectively studied. The association of protein (low: <0.8 g/kg/d, medium: 0.8–1.2 g/kg/d, high >1.2 g/kg/d) and energy intake (<80%, 80%–110%, 110% of target) during days 1–3 and 4–7 after ICU admission and 6‐month mortality was analyzed for septic and non‐septic patients separately. Results A total of 423 patients were investigated. Of these, 297 had sepsis. In the sepsis group, medium protein intake at days 4–7 was associated with lower 6‐month mortality (hazard ratio [HR]: 0.646, 95% confidence interval [CI]: 0.418‐0.996, P=0.048) compared with high intake. In the non‐sepsis group, early high and late low protein intake were associated with higher 6‐month mortality (HR: 3.902, 95% CI: 1.505‐10.115, P=0.005; HR: 2.642, 95% CI: 1.128‐6.189, P=0.025) compared with low and high protein intake, respectively. For energy intake, late energy intake of >110% was associated with decreased mortality in septic patients (HR: 0.400, 95% CI: 0.222‐0.721, P=0.002), whereas in non‐septic patients, late medium energy intake (80%–110%) was associated with better survival (HR: 0.379, 95% CI: 0.175‐0.820, P=0.014), both compared with low energy intake. Conclusion Divergent associations of macronutrient intake were found; early high protein intake in non‐septic patients, but not in septic patients, was found to be associated with higher 6‐month mortality.