Optimal route of supplementary protein delivery for physical recovery in critically ill patients: Protocol for a multicenter randomized clinical trial

BACKGROUND AND AIMS: Approximately 50% of critically ill patients develop physical impairment following intensive care. To overcome this impairment, major international guidelines for nutrition therapy recommend a higher protein intake than the standard dose. However, the optimal delivery route of additional protein supplementation to achieve protein target intake remains unclear. Therefore, this trial aims to identify the optimal route for supplementary protein delivery, either enteral nutrition (EN) alone or EN combined with parenteral amino acid supplementation, on physical outcomes. METHODS: This is a nationwide multicenter open-label randomized parallel-group trial. This study will encompass adult patients admitted to intensive care units in which EN can be initiated within 48 h of admission. Participants will be assigned to either the EN-only group (all protein provided enterally using high-protein EN formulas) or the EN + PN group (protein provided via EN combined with supplementary intravenous amino acids using standard-protein EN formulas) to achieve the target dose. The nutritional targets are 20-30 kcal/kg/day for energy and 1. 5-1. 8 g/kg/day for protein within 3-5 days post-EN initiation. The primary outcome is functional independence, defined as a Barthel Index score of ≥85, at 90 days following randomization. ETHICS AND DISSEMINATION: The Ethics Committee of Keio University School of Medicine approved this study (approval number: 20251054). Written informed consent will be obtained from all participants or their legal representatives. TRIAL REGISTRATION: This protocol was registered at the University Hospital Medical Information Network Clinical Trials Registry on July 12, 2025 (UMIN000058441: https: //center6. umin. ac. jp/cgi-open-bin/ctr/ctrᵥiew. cgi? recptno=R000066822).