Biological responses during high-dose protein nutrition in the critically ill: a randomized controlled trial

Reduced protein intake is associated with adverse outcomes in critically ill patients. Paradoxically, large-scale randomized controlled trials have failed to demonstrate a beneficial effect of protein supplementation, perhaps because the dose required to achieve an anabolic response is unknown, and because biological mechanisms that determine individual patient responses to nutrition are poorly understood.

The objective of this study was to determine the effect of exogenous protein dose on whole-body protein balance (WBPB) and associated biological markers of metabolic response.

We conducted a randomized controlled trial to determine the effect of high dose (2.5 g/kg/d by parenteral amino acid infusion for 48 h) compared with usual (0.8 g/kg/d) or moderate (1.75 g/kg/d) doses on WBPB. By measuring ¹³C-leucine stable isotope kinetics, whole-body protein synthesis and breakdown were evaluated before and after the intervention. As a comprehensive and well-annotated method to achieve untargeted biomarker identification, the blood transcriptome was interrogated by RNA sequencing every 12 h to identify molecular signatures associated with increases in WBPB during protein supplementation.

Thirty-three patients were randomly assigned, and 25 completed the study. The increase in WBPB for the high-dose group was 10.0±3.7, and that for the moderate and usual-dose groups were 6.7±2.9 and 6.6±3.6, μmol/kg/h (mean±SEM) respectively. After adjusting for baseline WBPB, high dose (P = 0.036 vs. usual dose, P = 0.047 vs. moderate dose), but not moderate dose (P = 0.893 vs. usual dose) protein led to larger increases in WBPB. Increased WBPB was associated with lower baseline protein balance (R² = 0.18, P = 0.03), and reduced expression of a distinct neutrophil bactericidal gene signature (normalized enrichment score = -1.613, P_adj = 0.003).

Larger increases in WBPB were observed in critically ill patients receiving a high-dose protein supplementation strategy, and these increases were associated with a biological program reflecting neutrophil-mediated bacterial killing.

ClinicalTrials.gov NCT02865408.