BACKGROUND: Injury severity induces a proportionate acute metabolic stress response, associated with increased risk of hyperglycemia. We hypothesized that excess caloric delivery (overfeeding) during high stress states would increase hyperglycemia and disrupt response homeostasis. METHODS: Gestational age, daily weight, total daily caloric intake, serum C-reactive protein (CRP), prealbumin, and blood glucose concentrations in all acutely-injured premature NICU infants requiring TPN over the past 3years were reviewed. Injury severity was based on CRP and patients were divided into high (CRP >/=50mg/L) versus low (CRP <50mg/L) stress groups. Glycemic variability was used to measure disruption of homeostasis. RESULTS: Overall sample included N=563 patient days (37 patients; 42 episodes). High stress group pre-albumin levels negatively correlated with CRP levels (R=-0.62, p<0.005). A test of equal variance demonstrated significantly increased high stress glycemic variability (Ha:ratio>1, Pr(F>f)=0.0353). When high stress patients were separated into high caloric intake (>/=70kg/kcal/day) versus low caloric intake (<70kg/kcal/day), maximum serum glucose levels were significantly higher with overfeeding (230.33+/-55.81 vs. 135.71+/-37.97mg/dL, p<0.004). CONCLUSION: Higher injury severity induces increased disruption of response homeostasis in critically ill neonates. TPN-associated overfeeding worsens injury-related hyperglycemia in more severely injured infants. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: Level II.